CoChat
Sign Up
Cited by 913Genetic and Kidney Cyst DiseasesCystic Fibrosis Research AdvancesHedgehog Signaling Pathway Studies

Cellular signalling by primary cilia in development, organ function and disease

Open access
Anvarian, Zeinab, Mykytyn, Kirk, Mukhopadhyay, Saikat, Pedersen, Lotte Bang, Christensen, Søren Tvorup·2019·Nature Reviews Nephrology
DOI 10.1038/s41581-019-0116-9PMC PMC6426138
Open this paper in CoChat — free account

Abstract

Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical Hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this Review, we highlight central mechanisms by which primary cilia coordinate HH, G protein-coupled receptor, WNT, receptor tyrosine kinase and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) signalling and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression.This Review describes the main signalling pathways that are coordinated by primary cilia to control developmental processes, tissue plasticity and organ function and how defects in the output of ciliary signalling events are coupled to developmental disorders and disease progression.Key pointsPrimary cilia emanate in a single copy from the centrosomal mother centriole (basal body) at the surface of most vertebrate cell types.Primary cilia possess a unique lipid and receptor composition and detect and convey extracellular cues to control cellular processes during development and in tissue homeostasis.Current evidence suggests that primary cilia coordinate a variety of signalling pathways, including those regulated by Hedgehog (HH), G protein-coupled receptors (GPCRs), WNT, receptor tyrosine kinases (RTKs) and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP), to control developmental processes, tissue plasticity and organ function.The ability of primary cilia to balance the output of cellular signalling is dynamic and relies on the differentiation state and microenvironment of the cell.Dysfunction of primary cilia underlies a pleiotropic group of diseases and syndromic disorders termed ciliopathies, affecting many different organs in the body.Mechanistic insight into ciliary coordination of spatiotemporal signalling networks is critical for understanding the aetiology of ciliopathies and for the discovery of novel ciliopathy disease genes and drug targets.

Integrity signals

Registry

Crossref · 10.1038/s41581-019-0116-9

Cites

307 of 307 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

187 of 312 cited sources checked · 45 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    The IFT-B complex proteins IFT25 and IFT27 are involved in ciliary export of hedgehog signalling components via retrograde IFT.

    “whereas the IFT-B complex proteins IFT25 and IFT27 are involved in ciliary export of hedgehog (HH) signalling components via retrograde IFT 59, 60, 62, 63.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [59] Liem, K. F. Jr. et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J. Cell Biol. 197, 789–800 (2012). source

      The Introduction (page unavailable) assigns anterograde trafficking to IFT-B and retrograde trafficking to IFT-A, contrary to the cited sentence’s assignment of retrograde export to IFT-B proteins. Our copy does not identify IFT25 or IFT27 or establish a specific exception for them. (LLM, conf=0.76)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [60] Keady, B. T. et al. IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev. Cell 22, 940–951 (2012). source

      The Introduction and Discussion report that IFT25 is required for ciliary export of the Hedgehog components Ptch1 and Smo. The Results show that IFT27 is depleted from cilia lacking IFT25, but the Discussion says IFT27’s contribution remains unclear. The paper presents export through IFT as a model, rather than directly establishing that both proteins mediate it via retrograde IFT. Page numbers were not available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [62] Bhogaraju, S. et al. Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. Science 341, 1009–1012 (2013). source

      Our copy’s Abstract discusses IFT74 and IFT81 binding tubulin and their role in ciliogenesis, not IFT25 or IFT27. Searches for IFT25/IFT27 and hedgehog-component export via retrograde IFT found no passage addressing the claim; page numbers are unavailable in the copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    The near-atomic-resolution structure of the human PC1-PC2 complex obtained by single-particle cryo-electron microscopy strongly favours a model in which PC1 and PC2 function together in regulating cation transport.

    “A report of the near-atomic-resolution structure of the human PC1-PC2 complex by single-particle cryo-electron microscopy, however, strongly favours a model in which PC1 and PC2 function together in regulating cation transport 94.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [94] Liu, X. et al. Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. eLife 7, e33183 (2018). source

      The Introduction describes a cryo-EM structure of PC2 alone as a homotetramer, not a near-atomic-resolution structure of a human PC1–PC2 complex. The Discussion section on loss of PC1 reports that PC1 is not essential for basal PC2 ciliary currents, contrary to the claim that this paper's structural evidence strongly favours their functioning together in cation transport. The authors do not exclude a possible association between them. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    The set of signalling components within the cilium is dynamic and closely coupled to the cell's differentiation state and microenvironment.

    “Emerging evidence indicates that the constellation of signalling components within the cilium is also dynamic and closely coupled to the differentiation state and microenvironment of the cell 3.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Heydeck, W., Fievet, L., Davis, E. E. & Katsanis, N. The complexity of the cilium: spatiotemporal diversity of an ancient organelle. Curr. Opin. Cell Biol. 55, 139–149 (2018). source

      The Concluding remarks describe the cilium as a dynamic organelle whose proteins interact in changing functional networks. “Unique spatiotemporal roles of ciliary proteins” links ciliation and Hedgehog signalling to differentiation and describes cilia restricted to particular extracellular-matrix zones. These passages do not establish that the specific set of signalling components within a cilium changes in close response to both differentiation state and microenvironment. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    Transition fibres mediate docking of the basal body to the plasma membrane or vesicles during early ciliogenesis.

    “For example, transition fibres mediate docking of the basal body to the plasma membrane or vesicles during early stages of ciliogenesis 4, 5”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [4] Sorokin, S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Biol. 15, 363–377 (1962). source

      The early-formation account (p. 365) says a primary ciliary vesicle attaches to the distal end of the centriole. The discussion (p. 374) also describes centriole attachment to the plasma membrane in another cell type, but questions whether attachment to the cell surface is obligatory. The paper does not identify transition fibres as mediating either attachment; it suggests that centriolar arms may help stabilize the centriole during cilium emergence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [5] Sorokin, S. P. Reconstructions of centriole formation and ciliogenesis in mammalian lungs. J. Cell Sci. 3, 207–230 (1968). source
  • Premisecitation

    Flagella in a Chlamydomonas bbs4 mutant show abnormal accumulation of several signalling proteins, resulting in disrupted phototaxis.

    “For example, flagella in a Chlamydomonas bbs4 mutant show abnormal accumulation of several signalling proteins, resulting in disrupted phototaxis 72.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [72] Lechtreck, K. F. et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J. Cell Biol. 187, 1117–1132 (2009). source

      The Introduction reports abnormal accumulation of several likely signaling proteins in BBS-mutant flagella and loss of phototaxis. The section on newly assembled bbs4-1 flagella reports transiently improved phototaxis, but says the accumulation *suggests* an impairment; the claim presents that proposed causal link as established. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • May combine two claims. 83
  • Borderline: one of the tests for a substantial claim is unclear. 1
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Premisecitation

    Ciliary JBN facilitates ciliary localization of beta-catenin following WNT3A stimulation and negatively affects WNT signalling.

    “Ciliary JBN facilitates the ciliary localization of β-catenin following WNT3A stimulation and thereby negatively affects WNT signalling 206.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [206] Lancaster, M. A. et al. Impaired Wnt–β-catenin signaling disrupts adult renal homeostasis and leads to cystic kidney ciliopathy. Nat. Med. 15, 1046 (2009). source

      In Results, ‘Jbn facilitates β-catenin nuclear translocation’ (page unavailable), the paper reports that Jbn enhances Wnt3a-dependent β-catenin accumulation in the nucleus, not the cilium. In Results, ‘Jbn functions downstream of β-catenin stabilization’ (page unavailable), it reports that Jbn potentiates the response to Wnt3a and positively modulates canonical Wnt signaling, contrary to the claimed negative effect. (LLM, conf=0.90)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Borderline on S3 (load-bearing): unclear from the text. May combine two claims.

    Premisecitation

    Dopamine receptor type 5 localizes to cilia on renal epithelial cells and may functionally couple to the CaV1.2 L-type calcium channel.

    “Dopamine receptor type 5 (D5) localizes to cilia on renal epithelial cells, where it may functionally couple to the CaV1.2 L-type calcium channel 160.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [160] Masyuk, A. I. et al. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1013–G1024 (2013). source

      The Abstract and Discussion describe TGR5 localization and signaling in cholangiocyte cilia, not dopamine receptor D5 in renal epithelial cilia. Searches for D5 and CaV1.2 found no passage addressing their localization or functional coupling; the Discussion mentions renal epithelial cilia only in relation to cAMP signaling. No page numbers were provided in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In cells that form a single primary cilium, the basal body comes from the mother centriole, and axoneme extension can begin before or after basal body docking depending on cell type.

    “For cells that form a single primary cilium (Figure 1), the basal body is derived from the mother centriole of the centrosome, and depending on the cell type, axoneme extension can be initiated before or after docking of the basal body at the plasma membrane 4, 5.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [4] Sorokin, S. Centrioles and the formation of rudimentary cilia by fibroblasts and smooth muscle cells. J. Cell Biol. 15, 363–377 (1962). source

      Phase II (pp. 369–370) describes a ciliary shaft growing from one centriole before the cilium reaches the cell surface. The discussion (p. 374) contrasts this with a reported neuroepithelial sequence in which the centriole first attaches to the cell membrane. The paper does not identify the cilium-forming centriole as the mother centriole, and its description of shaft growth does not establish when axoneme extension begins. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [5] Sorokin, S. P. Reconstructions of centriole formation and ciliogenesis in mammalian lungs. J. Cell Sci. 3, 207–230 (1968). source

  • May combine two claims.

    Premisecitation

    Quiescent cells can lose their cilium due to developmental programming or environmental insults such as mechanical stress.

    “Quiescent cells can lose their cilium as a consequence of developmental programming 15–19 or in response to environmental insults such as mechanical stress 20.”
    Quote in the paperNot a substantial claim5 of 6 sources checked
    • cites [15] Das, R. M. & Storey, K. G. Apical abscission alters cell polarity and dismantles the primary cilium during neurogenesis. Science 343, 200–204 (2014). source

      The Abstract and a main-text passage indexed under Abstract (page unavailable) show that apical abscission dismantles the primary cilium during neuronal differentiation. They place cilium disassembly before cell-cycle exit, however, so the paper does not establish cilium loss in already quiescent cells. The mechanical-stress clause has a separate citation and is not attributed to this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] McDermott, K. M., Liu, B. Y., Tlsty, T. D. & Pazour, G. J. Primary cilia regulate branching morphogenesis during mammary gland development. Curr. Biol. 20, 731–737 (2010). source

      The citation to this paper is attached to the claim that mechanical stress can cause quiescent cells to lose their cilium. The Results and Discussion describe reduced cilia in mice with an IFT88 mutation and developmental regression of cilia in rodent ear hair cells, but the passages found by searching for mechanical stress and environmental insults do not address stress-induced cilium loss. (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [17] Blitzer, A. L. et al. Primary cilia dynamics instruct tissue patterning and repair of corneal endothelium. Proc. Natl Acad. Sci. USA 108, 2819–2824 (2011). source
    • cites [18] Bangs, F. K., Schrode, N., Hadjantonakis, A. K. & Anderson, K. V. Lineage specificity of primary cilia in the mouse embryo. Nat. Cell Biol. 17, 113–122 (2015). source

      The Discussion (page unavailable) says cilia formation is controlled by stable lineage-based mechanisms and that visceral endoderm and XEN cells fail to form cilia. This supports developmental control of ciliation, but the paper does not establish that quiescent cells lose a cilium they previously had. The mechanical-stress clause has a separate citation and is not assessed against this source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] May-Simera, H. L. et al. Primary cilium-mediated retinal pigment epithelium maturation is disrupted in ciliopathy patient cells. Cell Rep. 22, 189–205 (2018). source

      The citation range 15–19 is attached to developmental programming; mechanical stress has a separate citation (20). The Results section, “Primary Cilium Induction Helps Generate Fully Mature and Functional hiPSC-Derived RPE” (page unavailable), says cilia emerge as RPE cells mature, but does not say quiescent cells lose cilia through developmental programming. Searches for cilium loss and quiescence found no passage establishing that point. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [20] Iomini, C., Tejada, K., Mo, W., Vaananen, H. & Piperno, G. Primary cilia of human endothelial cells disassemble under laminar shear stress. J. Cell Biol. 164, 811–817 (2004). source

  • May combine two claims.

    Premisecitation

    Before mitosis, the cilium is usually dismantled and centrioles are duplicated for mitotic spindle pole formation.

    “before mitosis the cilium is usually dismantled and centrioles are duplicated for participation in mitotic spindle pole formation 9–14.”
    Quote in the paperNot a substantial claim3 of 6 sources checked
    • cites [9] Tucker, R. W., Pardee, A. B. & Fujiwara, K. Centriole ciliation is related to quiescence and DNA synthesis in 3T3 cells. Cell 17, 527–535 (1979). source
    • cites [10] Rieder, C. L., Jensen, C. G. & Jensen, L. C. The resorption of primary cilia during mitosis in a vertebrate (PtK1) cell line. J. Ultrastruct. Res. 68, 173–185 (1979). source
    • cites [11] Tucker, R. W., Scher, C. D. & Stiles, C. D. Centriole deciliation associated with the early response of 3T3 cells to growth factors but not to SV40. Cell 18, 1065–1072 (1979). source
    • cites [12] Pugacheva, E. N., Jablonski, S. A., Hartman, T. R., Henske, E. P. & Golemis, E. A. HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell 129, 1351–1363 (2007). source

      The Introduction says that in many cells cilia are resorbed at mitotic entry, supporting the cilium-disassembly part of the claim. It identifies the basal body as arising from a centriole, but does not say that centrioles are duplicated for mitotic spindle pole formation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [13] Spalluto, C., Wilson, D. I. & Hearn, T. Evidence for reciliation of RPE1 cells in late G1 phase, and ciliary localisation of cyclin B1. FEBS Open Bio 3, 334–340 (2013). source
    • cites [14] Ford, M. J. et al. A cell/cilia cycle biosensor for single-cell kinetics reveals persistence of cilia after G1/S transition is a general property in cells and mice. Dev. Cell 47, 509–523 (2018). source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The three-dimensional structures of many IFT-B polypeptides have been solved, and progress has been made in understanding the arrangement and interactions of individual IFT polypeptides within the IFT-A and IFT-B sub-complexes.

    “The three dimensional structures of many IFT-B polypeptides have been solved, and progress has been made towards understanding the arrangement and interactions of individual IFT polypeptides within the IFT-A and IFT-B sub-complexes 25.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Taschner, M. & Lorentzen, E. The intraflagellar transport machinery. Cold Spring Harb. Perspect. Biol. 8, a028092 (2016). source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Subsequent work in protists and metazoans, including Tetrahymena, Trypanosoma, C. elegans, sea urchin, zebrafish, mouse and human, substantiated the evolutionary conservation of IFT and provided insight into its molecular workings and physiological roles.

    “Subsequent work in a range of additional organisms, including protists such as Tetrahymena thermophila and Trypanosoma brucei and metazoans like C. elegans, sea urchin, zebrafish, mouse, and human, have substantiated this view, and provided remarkable insight into the molecular workings and physiological roles of IFT 25, 30, 31, 46.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [25] Taschner, M. & Lorentzen, E. The intraflagellar transport machinery. Cold Spring Harb. Perspect. Biol. 8, a028092 (2016). source

      The paper’s discovery and IFT-A sections describe IFT findings in Tetrahymena, Trypanosoma, C. elegans, zebrafish and mammals, including molecular functions and disease relevance (page unavailable in our copy). Its only sea-urchin mention is a reference to a kinesin purified from sea-urchin eggs; it does not describe sea-urchin work substantiating IFT conservation or clarifying IFT’s roles. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [30] Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008). source
    • cites [31] Prevo, B., Scholey, J. M. & Peterman, E. J. G. Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. FEBS J. 284, 2905–2931 (2017). source

      Section 7 (IFT in different Model Systems; page unavailable) describes IFT studies across protists, C. elegans, sea urchins, zebrafish, and mice, and says direct assays in several systems have yielded mechanistic insight. Its Protists subsection covers Trypanosoma, and its references identify an IFT assay in Tetrahymena. The passages support the broad cross-eukaryote point, but do not document human work as part of the claimed subsequent studies. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Early work using Chlamydomonas and C. elegans mutants suggested IFT-A and IFT-B function in retrograde and anterograde IFT, respectively, but these polypeptides are now known to participate in ciliary transport in both directions.

    “For example, although early work using C. reinhardtii and C. elegans mutants suggested that IFT-A and IFT-B complexes function in retrograde and anterograde IFT, respectively 30, 46, we now know that these polypeptides participate in ciliary transport in both directions 54–60.”
    Quote in the paperNot a substantial claim3 of 9 sources checked
    • cites [30] Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008). source
    • cites [46] Rosenbaum, J. L. & Witman, G. B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 3, 813–825 (2002). source
    • cites [54] Perkins, L. A., Hedgecock, E. M., Thomson, J. N. & Culotti, J. G. Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev. Biol. 117, 456–487 (1986). source
    • cites [55] Pedersen, L. B. et al. Chlamydomonas IFT172 is encoded by FLA11, interacts with CrEB1, and regulates IFT at the flagellar tip. Curr. Biol. 15, 262–266 (2005). source
    • cites [56] Qin, H. et al. Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr. Biol. 15, 1695–1699 (2005). source
    • cites [57] Mukhopadhyay, S. et al. TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia. Genes Dev. 24, 2180–2193 (2010). source

      In “TULP3 is an effector of the IFT-A complex” (page unavailable), the paper says IFT-A provides ciliary access to TULP3 in addition to its known retrograde role, supporting a role for IFT-A in both directions. The introductory discussion describes IFT-B proteins accumulating when retrograde transport is impaired, but does not establish that IFT-B itself functions in both directions. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [58] Behal, R. H. et al. Subunit interactions and organization of the Chlamydomonas reinhardtii intraflagellar transport complex A proteins. J. Biol. Chem. 287, 11689–11703 (2012). source
    • cites [59] Liem, K. F. Jr. et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. J. Cell Biol. 197, 789–800 (2012). source

      The Discussion section “IFT144 is required for anterograde, as well as retrograde, ciliary trafficking” supports a role for IFT-A in both directions and describes IFT-B as participating in anterograde trafficking. It does not establish that IFT-B participates in retrograde trafficking, so it supports only part of the claim attributed to this source. Page numbers were not available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [60] Keady, B. T. et al. IFT25 links the signal-dependent movement of Hedgehog components to intraflagellar transport. Dev. Cell 22, 940–951 (2012). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    These IFT polypeptides can be subdivided into IFT-A, IFT-B1 and IFT-B2 sub-complexes containing 6, 10 and 6 different IFT particle proteins, respectively.

    “We now know these polypeptides can be subdivided into IFT-A, IFT-B1 and IFT-B2 sub-complexes that contain 6, 10 and 6 different IFT particle proteins, respectively 25, 30, 31, 46, 47.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [25] Taschner, M. & Lorentzen, E. The intraflagellar transport machinery. Cold Spring Harb. Perspect. Biol. 8, a028092 (2016). source
    • cites [30] Pedersen, L. B. & Rosenbaum, J. L. Intraflagellar transport (IFT) role in ciliary assembly, resorption and signalling. Curr. Top. Dev. Biol. 85, 23–61 (2008). source
    • cites [31] Prevo, B., Scholey, J. M. & Peterman, E. J. G. Intraflagellar transport: mechanisms of motor action, cooperation, and cargo delivery. FEBS J. 284, 2905–2931 (2017). source

  • May combine two claims.

    Premisecitation

    Many studies in different organisms confirmed a universal requirement for heterotrimeric kinesin-2 and cytoplasmic dynein 2 in IFT, but some organisms also use accessory kinesins to regulate aspects of ciliary assembly or function.

    “A large number of studies in different organisms subsequently confirmed a universal requirement for these motors in IFT, but also demonstrated that some organisms additionally use ‘accessory’ kinesins to regulate certain aspects of ciliary assembly or function 23, 39.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [23] Morthorst, S. K., Christensen, S. T. & Pedersen, L. B. Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins. FEBS J. 285, 4535–4564 (2018). source

      The “Intraflagellar transport” section (page not available) describes kinesin-2 and dynein 2 as IFT motors, but says mutations in their subunits usually cause severe ciliary defects in most organisms studied—not that their requirement is universal. The “Role of kinesin-2 motors in axoneme extension” section (page not available) describes additional kinesin-2 motors with overlapping or partially redundant roles in some organisms, supporting the accessory-motor part of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [39] Verhey, K. J., Dishinger, J. & Kee, H. L. Kinesin motors and primary cilia. Biochem. Soc. Trans. 39, 1120–1125 (2011). source

      The Intraflagellar transport section (page unavailable) says heterotrimeric kinesin-2 is critical for anterograde IFT in every organism tested and identifies cytoplasmic dynein as the retrograde IFT motor. The IFT kinesins section (page unavailable) describes accessory kinesins with cell-specific roles in ciliary shape and function. The copy does not establish the claimed universal requirement for cytoplasmic dynein across organisms. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    BBSome proteins were initially thought to facilitate delivery of GPCRs to cilia, but it has been proposed that they primarily regulate ciliary export of signalling proteins.

    “The BBSome proteins were initially thought to facilitate the delivery of GPCRs to cilia 73–75; however, it has been proposed that BBSome proteins primarily regulate ciliary export of signalling proteins 72, 76, 77, 78.”
    Quote in the paperNot a substantial claim4 of 4 sources checked
    • cites [72] Lechtreck, K. F. et al. The Chlamydomonas reinhardtii BBSome is an IFT cargo required for export of specific signaling proteins from flagella. J. Cell Biol. 187, 1117–1132 (2009). source
    • cites [76] Lechtreck, K. F. et al. Cycling of the signaling protein phospholipase D through cilia requires the BBSome only for the export phase. J. Cell Biol. 201, 249–261 (2013). source

      The Discussion (page unavailable) proposes that BBSome-mediated export may apply to many cycling membrane-associated proteins, supporting the cited export proposal. It does not establish that export is the BBSome’s primary role across signalling proteins; the Introduction says both import and export of ciliary GPCRs may be affected. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [77] Nachury, M. V. The molecular machines that traffic signaling receptors into and out of cilia. Curr. Opin. Cell Biol. 51, 124–131 (2018). source
    • cites [78] Wingfield, J. L., Lechtreck, K.-F. & Lorentzen, E. Trafficking of ciliary membrane proteins by the intraflagellar transport/BBSome machinery. Essays Biochem. 62, 753–763 (2018). source

  • May combine two claims.

    Premisecitation

    Progress has been made in understanding interactions between specific IFT particle polypeptides and specific ciliary cargo proteins or motor subunits during anterograde or retrograde IFT, as well as how IFT motor activity is regulated.

    “Likewise, progress has been made towards understanding the interactions between specific IFT particle polypeptides and specific ciliary cargo proteins or motor subunits during anterograde or retrograde IFT, as well as how IFT motor activity is regulated 24, 48–52.”
    Quote in the paperNot a substantial claim6 of 6 sources checked
    • cites [24] Lechtreck, K. F. IFT-cargo interactions and protein transport in cilia. Trends Biochem. Sci. 40, 765–778 (2015). source

      The sections on cargo binding and known IFT binding sites describe specific interactions, including IFT81/IFT74 with tubulin and IFT46 with an adaptor for outer dynein arms. The building-blocks section identifies the motors for anterograde and retrograde transport, but the paper does not substantively explain how IFT motor activity is regulated or establish the claimed interactions with specific motor subunits. Page numbers were unavailable in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [48] Bhogaraju, S., Engel, B. D. & Lorentzen, E. Intraflagellar transport complex structure and cargo interactions. Cilia 2, 10 (2013). source
      Experimental — accuracy not yet measured
    • cites [49] Toropova, K., Mladenov, M. & Roberts, A. J. Intraflagellar transport dynein is autoinhibited by trapping of its mechanical and track-binding elements. Nat. Struct. Mol. Biol. 24, 461–468 (2017). source
      Experimental — accuracy not yet measured
    • cites [50] Funabashi, T., Katoh, Y., Okazaki, M., Sugawa, M. & Nakayama, K. Interaction of heterotrimeric kinesin-II with IFT-B-connecting tetramer is crucial for ciliogenesis. J. Cell Biol. 217, 2867–2876 (2018). source
      Experimental — accuracy not yet measured
    • cites [51] Mohamed, M. A. A., Stepp, W. L. & Okten, Z. Reconstitution reveals motor activation for intraflagellar transport. Nature 557, 387–391 (2018). source
      Experimental — accuracy not yet measured
    • cites [52] Liang, Y., Zhu, X., Wu, Q. & Pan, J. Ciliary length sensing regulates IFT entry via changes in FLA8/KIF3B phosphorylation to control ciliary assembly. Curr. Biol. 28, 2429–2435 (2018). source

      The Results and Discussion report that FLA8/KIF3B phosphorylation regulates IFT entry and that phosphatase knockdown reduces anterograde and retrograde IFT velocities. The paper also discusses kinesin-II interaction with IFT-B, but our copy does not establish specific IFT-particle-polypeptide interactions with ciliary cargo proteins or retrograde motor subunits. No page number is available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    HH signalling can occur through non-canonical pathways involving either GLI-independent mechanisms or SMO-independent regulation of GLI activity.

    “In addition to canonical pathways, HH signalling can occur though so-called non-canonical pathways, which involve either GLI-independent mechanisms or SMO-independent regulation of GLI activity 106, 107.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [106] Bitgood, M. J. & McMahon, A. P. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev. Biol. 172, 126–138 (1995). source
    • cites [107] Carballo, G. B., Honorato, J. R., de Lopes, G. P. F. & Spohr, T. C. L. S. E. A highlight on Sonic hedgehog pathway. Cell Commun. Signal. 16, 11 (2018). source

      The “Non-canonical Shh signaling” section and Fig. 2 describe GLI-independent mechanisms, including a SMO-independent type. They do not describe SMO-independent regulation of GLI activity; their SMO-independent example is also GLI-independent. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The extracellular domains of PTCH1 also have an interface that accommodates cholesterol derivatives, and binding of PTCH1 to the SHH N-fragment potentially limits access to or exit of these derivatives from this site.

    “Interestingly, the extracellular domains also have an interface that accommodates cholesterol derivatives, and binding of PTCH1 to the N-fragment of SHH potentially limits access to or exit of these derivatives from this site.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018). source

      The Introduction (page unavailable) says that SHH binds PTCH1, but it does not describe PTCH1’s extracellular structure or a cholesterol-derivative binding site. Searches for the proposed interface and for cholesterol or sterol access found no passage addressing whether SHH binding limits entry to or exit from such a site. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The two extracellular domains of PTCH1 interact with SHH, although two structural studies identified different interacting interfaces with native lipidated SHH and an SHH N-fragment.

    “The two extracellular domains of PTCH1 interact with SHH, although the two structural studies that investigated SHH binding identified different interacting interfaces with native lipidated SHH and an SHH N-fragment 111, 112.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [111] Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018). source

      The Introduction (page unavailable) says that Hedgehog proteins, including SHH, bind PTCH1. It does not describe PTCH1’s two extracellular domains or compare binding interfaces identified by structural studies using lipidated SHH and an SHH N-fragment. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [112] Gong, X. et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 361, eaas8935 (2018). source

  • May combine two claims.

    Premisecitation

    PTCH1 shows similarity to members of the RND family of bacterial efflux transporters and to sterol sensing domains in the cholesterol trafficking protein NPC1.

    “First, PTCH1 shows similarity to members of the resistance-nodulation-cell division (RND) family of bacterial efflux transporters and to sterol sensing domains in the cholesterol trafficking protein, Niemann-Pick C1 (NPC1).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [111] Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018). source

      The Introduction describes PTCH1 as a 12-transmembrane Hedgehog receptor, but does not discuss its structural similarity to other proteins. Searches for RND bacterial efflux transporters and NPC1 sterol-sensing domains found no passage addressing either comparison in our copy; page numbers were not available. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [112] Gong, X. et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 361, eaas8935 (2018). source

  • May combine two claims.

    Premisecitation

    The intermediate steps between SMO activation, GLIA formation and translocation to the nucleus are not well understood, although GLI2 and GLI3 proteins accumulate in cilia tips upon HH pathway activation, suggesting that GLIA formation is regulated near cilia.

    “The intermediate steps between SMO activation, GLIA formation and translocation to the nucleus are not well understood, although GLI2 and GLI3 proteins accumulate in cilia tips upon HH pathway activation, suggesting that GLIA formation is regulated in the vicinity of cilia 117.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [117] Dorn, K. V., Hughes, C. E. & Rohatgi, R. A. Smoothened-Evc2 complex transduces the Hedgehog signal at primary cilia. Dev. Cell 23, 823–835 (2012). source

  • May combine two claims.

    Premisecitation

    Binding of PTCH1 to the SHH N-fragment is enhanced by cholesterol derivatives, and it is predicted that binding of cholesterol to the extracellular domain interface might arise from cholesterol transport by PTCH1.

    “Binding of PTCH1 to the N-fragment of SHH is enhanced by cholesterol derivatives and it is predicted that binding of cholesterol to the extracellular domain interface might arise from cholesterol transport by PTCH1 111.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [111] Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018). source

      The Introduction (page unavailable) says that Hedgehog proteins, including SHH, bind PTCH1. It does not specify the SHH N-fragment, say that cholesterol derivatives enhance binding, or predict cholesterol binding at an extracellular-domain interface through PTCH1 transport. Searches for those cholesterol-related claims found no supporting passage. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Transmembrane segments 2-6 in PTCH1 constitute the sterol-sensing domain and are sufficient to accommodate cholesterol derivatives.

    “The transmembrane segments 2–6 in PTCH1 constitute the sterol-sensing domain, and are sufficient to accommodate cholesterol derivatives 111, 112.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [111] Ho Wei, L., Arastoo, M., Georgiou, I., Manning, D. R. & Riobo-Del Galdo, N. A. Activation of the Gi protein-RHOA axis by non-canonical Hedgehog signaling is independent of primary cilia. PLOS ONE 13, e0203170 (2018). source

      The Introduction describes PTCH1 as a 12-transmembrane receptor, but does not identify segments 2–6 as a sterol-sensing domain or say they accommodate cholesterol derivatives. Searches for those terms in our copy found no passage addressing the claimed structure or binding capacity; the Results instead concern Smoothened signaling outside primary cilia. Page numbers were not available in the indexed copy. (LLM, conf=0.75)

      Experimental — accuracy not yet measured
    • cites [112] Gong, X. et al. Structural basis for the recognition of Sonic Hedgehog by human Patched1. Science 361, eaas8935 (2018). source

  • May combine two claims.

    Premisecitation

    GPR175 is enriched in cilia in the presence of SHH and might regulate maximal activation of pathways downstream of SMO by coupling to Gαi, leading to decreased cAMP levels and inhibiting PKA-mediated formation of GLI3R.

    “Furthermore, the 7-transmembrane receptor GPR175 (also known as TPRA1 or TPRA40) is enriched in cilia in the presence of SHH, and might regulate maximal activation of pathways downstream of SMO by coupling to the inhibitory Gα protein, Gαi, leading to decreased cAMP levels and inhibiting PKA-mediated formation of GLI3R 116.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [116] Zhang, Y. et al. Structural basis for cholesterol transport-like activity of the hedgehog receptor Patched. Cell 175, 1352–1364 (2018). source

      The Abstract and ‘Redistribution of membrane cholesterol by PTCH1’ section discuss SHH, PTCH1, and SMO regulation, but do not address GPR175. Searches for GPR175/TPRA1/TPRA40 and Gαi/cAMP/PKA/GLI3R found no passage supporting the claimed ciliary enrichment or signaling mechanism. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    CAV1 localizes to the base of cilia in cultured mammalian cells in a manner dependent on KIF13B, and both CAV1 and KIF13B have been implicated in regulation of SHH signalling.

    “CAV1 localizes to the base of cilia in cultured mammalian cells in a manner dependent on the kinesin-3 motor protein KIF13B; both CAV1 and KIF13B have been implicated in the regulation of SHH signalling 99.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [99] Yue, S. et al. Requirement of Smurf-mediated endocytosis of Patched1 in sonic hedgehog signal reception. eLife 3, e02555 (2014). source

      The Results section on Ptch1 accumulation in lipid rafts reports that Shh treatment increases Ptch1 colocalization with Cav-1, and the Discussion links Cav-1-positive lipid rafts to Shh-related Ptch1 trafficking. Our copy does not establish that Cav-1 localizes to the ciliary base, that its localization depends on KIF13B, or that KIF13B regulates SHH signalling (searched: KIF13B and Caveolin-1 ciliary base). The supplied passages have no page numbers. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Binding of SHH to PTCH1 triggers endocytic clearance of PTCH1 from the cilium, relying on ubiquitination of the receptor by SMURF1 and SMURF2, which co-localize with PTCH1 in CAV1-positive lipid rafts and vesicles.

    “Binding of SHH to its 12-transmembrane receptor Patched-1 (PTCH1) triggers endocytic clearance of PTCH1 from the cilium in a process that relies on ubiquitination of the receptor by the HECT domain E3 ubiquitin ligases SMURF1 and SMURF2, which co-localize with PTCH1 in caveolin-1 (CAV1)-positive lipid rafts and vesicles 98.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [98] Goetz, S. C. & Anderson, K. V. The primary cilium: a signalling centre during vertebrate development. Nat. Rev. Genet. 11, 331–344 (2010). source

      In “Enrichment of Hh pathway components in cilia” (page unavailable), the paper says Ptch1 is the Hh receptor and exits the cilium upon exposure to ligand. It does not describe that exit as endocytic clearance or attribute it to SMURF1/SMURF2-mediated ubiquitination or co-localization in CAV1-positive lipid rafts and vesicles. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A longitudinal tunnel capable of accommodating cholesterol was identified in the transmembrane region of active SMO, suggesting that SMO itself might move cholesterol from the plasma membrane to the extracellular domain.

    “Interestingly, a longitudinal tunnel capable of accommodating cholesterol was identified in the transmembrane region of active SMO, suggesting that SMO itself might move cholesterol from the plasma membrane to the extracellular domain 113.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [113] Qi, X., Schmiege, P., Coutavas, E., Wang, J. & Li, X. Structures of human Patched and its complex with native palmitoylated sonic hedgehog. Nature 560, 128–132 (2018). source

      The passage describing a hydrophobic pocket (section labeled Abstract; page unavailable) locates it in Ptch1, not active SMO. A further passage says the mechanism of SMO inhibition remains poorly understood. Searches for a longitudinal tunnel in SMO and cholesterol movement through SMO found no passage addressing either claim in our copy. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Oxysterols can bind to the cysteine-rich domain and activate SMO downstream and independent of PTCH1 removal from cilia, but the physiological role of oxysterols in HH pathway activation is not clear.

    “Oxysterols can also bind to the cysteine rich domain and activate SMO downstream and independent of PTCH1 removal from cilia 102, 114; however, the physiological role of oxysterols in HH pathway activation is not clear.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [102] Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005). source
    • cites [114] Huang, P. et al. Structural basis of Smoothened activation in Hedgehog signaling. Cell 174, 312–324 (2018). source

      The Results section, “Allosteric activation of the 7TM domain by sterol-bound CRD” (page unavailable), reports that 20(S)-hydroxycholesterol activates SMO and that oxysterol-bound CRD allosterically activates its 7TM domain. The paper does not establish that this occurs independently of PTCH1 removal from cilia, nor does it specifically state that oxysterols’ physiological role in HH activation is unclear. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CAV1 has been reported to have ciliary functions in C. elegans.

    “CAV1 has also been reported to have ciliary functions in C. elegans 100.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [100] Schou, K. B. et al. KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling. Nat. Commun. 8, 14177 (2017). source

      The Results section on KIF13B and NPHP4 reports CAV1 at the ciliary transition zone in RPE1 cells, supporting a ciliary role for CAV1. The paper’s C. elegans passages instead discuss KLP-6 and polycystin-2; they do not report a ciliary function for CAV1 in that species. No page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Removal of ciliary PTCH1 in response to SHH binding is associated with ciliary enrichment of SMO, a 7-transmembrane receptor of the class F frizzled GPCR family, leading to GLIA formation predominantly by phosphorylation of GLI2.

    “Removal of ciliary PTCH1 in response to SHH binding is associated with ciliary enrichment of Smoothened (SMO) 101, 102 –a 7-transmembrane receptor belonging to the class F (frizzled) family of GPCRs – which ultimately leads to the formation of GLIA, predominantly by phosphorylation of GLI2 103 (Figure 2).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [101] Scheidel, N., Kennedy, J. & Blacque, O. E. Endosome maturation factors Rabenosyn-5/VPS45 and caveolin-1 regulate ciliary membrane and polycystin-2 homeostasis. EMBO J. 37, e98248 (2018). source

      The Introduction states that Shh activation causes Ptch1 to leave the cilium as Smo enters it, supporting the trafficking portion of the claim. Our copy does not identify Smo as a class F frizzled GPCR or describe GLIA formation through GLI2 phosphorylation; the printed sentence places a separate citation after that downstream claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [102] Corbit, K. C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005). source
    • cites [103] Rohatgi, R., Milenkovic, L. & Scott, M. P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007). source

  • May combine two claims.

    Premisecitation

    Absence of GPR161, PKA, and SUFU induces high levels of SHH signalling during mouse neural tube development, similar to the effect of Ptch1 deletion, which induces activation of SMO signalling.

    “Importantly, the absence of GPR161, PKA, and SUFU induces high levels of SHH signalling during mouse neural tube development 122, 125, 126, similar to the effect of Ptch1 deletion, which induces activation of SMO signalling 127.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [122] Pan, Y. & Wang, B. A novel protein-processing domain in Gli2 and Gli3 differentially blocks complete protein degradation by the proteasome. J. Biol. Chem. 282, 10846–10852 (2007). source

      Our copy discusses PKA-dependent Gli3 processing in the Hedgehog pathway (Abstract; Figure 1 caption), but does not report that loss of PKA, GPR161, or SUFU causes high SHH signalling in the developing mouse neural tube. Searches for neural-tube signalling and the named proteins also found no passage supporting the comparison with Ptch1 deletion and SMO activation. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [125] Humke, E. W., Dorn, K. V., Milenkovic, L., Scott, M. P. & Rohatgi, R. The output of Hedgehog signaling is controlled by the dynamic association between Suppressor of Fused and the Gli proteins. Genes Dev. 24, 670–682 (2010). source

      The introduction (page unavailable) says that genetic inactivation of Sufu constitutively activates Hedgehog target genes in mice, supporting the SUFU portion of the claim. The paper does not establish this specifically during mouse neural tube development, and its PKA experiments manipulate activity in cultured cells rather than test PKA absence in the neural tube. The Ptch1 comparison has a separate citation in the citing sentence. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [126] Jia, J. et al. Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev. Biol. 330, 452–460 (2009). source

  • May combine two claims.

    Premisecitation

    KIF7 becomes enriched at ciliary tips during Hedgehog pathway activation and acts as both a positive and negative regulator of SHH signalling by modifying ciliary architecture.

    “KIF7, also becomes enriched in ciliary tips during activation of HH signalling 136, 137, where it. functions as both a positive and negative regulator of SHH signalling by modifying ciliary architecture 136, 137.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [136] Hwang, S. H. et al. The G protein-coupled receptor Gpr161 regulates forelimb formation, limb patterning and skeletal morphogenesis in a primary cilium-dependent manner. Development 145, dev154054 (2018). source

      The Introduction (page unavailable) discusses ciliary Hedgehog signalling and describes Smoothened enrichment in cilia, but does not make the claimed point about KIF7. Searches for KIF7, ciliary-tip enrichment, and its proposed positive and negative effects through ciliary architecture found no passage addressing those claims. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [137] Shimada, I. S. et al. Basal suppression of the Sonic Hedgehog pathway by the G-protein-coupled receptor Gpr161 restricts medulloblastoma pathogenesis. Cell Rep. 22, 1169–1184 (2018). source

      The Introduction discusses cilium-dependent activation and repression of SHH signalling, but does not attribute either role to KIF7. Searches for KIF7, its enrichment at ciliary tips, and its effect on ciliary architecture found no passage addressing those claims; the Discussion instead mentions Kif3a and Gpr161. Page numbers were not available in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The neural tube ventralization phenotypes of Tulp3 and IFT-A mutants and Gpr161 mutants are weaker than those resulting from mutations in downstream negative regulators of HH signalling such as Sufu and PKA, suggesting additional inputs into PKA activation other than GPR161.

    “However, the neural tube ventralization phenotypes of Tulp3 and IFT-A mutants, and Gpr161 mutants are weaker than those resulting from mutations in downstream negative regulators of HH signalling such as Sufu and PKA 132, suggesting the existence of additional inputs into PKA activation other than GPR161 133.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [132] Qin, J., Lin, Y., Norman, R. X., Ko, H. W. & Eggenschwiler, J. T. Intraflagellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc. Natl Acad. Sci. USA 108, 1456–1461 (2011). source
    • cites [133] Ocbina, P. J. R., Eggenschwiler, J. T., Moskowitz, I. & Anderson, K. V. Complex interactions between genes controlling trafficking in primary cilia. Nat. Genet. 43, 547–553 (2011). source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Premature SHH signalling resulting from disruption of GPR161 causes defects in limb and skeletal morphogenesis, cerebellar granule cell hyperproliferation and formation of SHH-subtype medulloblastoma.

    “The importance of HH pathway repression is illustrated by the finding that premature SHH signalling resulting from disruption of GPR161 causes defects in limb and skeletal morphogenesis 134, cerebellar granule cell hyper-proliferation and formation of SHH-subtype medulloblastoma 135.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [134] Hwang, S. H. & Mukhopadhyay, S. G-Protein-coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning. Birth Defects Res. A Clin. Mol. Teratol 103, 12–19 (2015). source
    • cites [135] Pusapati, G. V. et al. G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog. Sci. Signal. 11, eaao5749 (2018). source

      The Results section on GPR161 in neural progenitor cells (page unavailable) reports that GPR161 loss increases Hedgehog signalling and alters neural progenitor specification. The Introduction mentions limb-bud patterning by Hedgehog ligands, but our copy does not link GPR161 disruption to limb or skeletal defects. The cerebellar proliferation and medulloblastoma findings carry a separate citation (135), so they are not attributed to this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activation of GPBAR1 on ciliated cholangiocytes induces co-localization with Gαi, decreases cAMP signalling, activates ERK signalling, and decreases proliferation.

    “activation of GPBAR1 on ciliated cells induced co-localization of GPBAR1 with Gαi, decreased cAMP signalling, activated ERK signalling, and decreased cellular proliferation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [155] Schou, K. B., Pedersen, L. B. & Christensen, S. T. Ins and outs of GPCR signaling in primary cilia. EMBO Rep. 16, 1099–1113 (2015). source

      The Introduction (page unavailable) reports that TGR5 ligand treatment in ciliated cholangiocytes decreased cAMP levels and proliferation while activating ERK signaling. The paper identifies TGR5 as GPBAR1, but the passages do not report that activation induced co-localization with Gαi. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PKA activation in different subcellular regions is mediated by local cAMP production and anchoring of PKA to AKAPs.

    “Activation of PKA in different subcellular regions is mediated by local cAMP production and anchoring of PKA to A-kinase anchoring proteins (AKAPs) 141.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [141] Garcia-Gonzalo, F. R. et al. Phosphoinositides regulate ciliary protein trafficking to modulate Hedgehog signaling. Dev. Cell 34, 400–409 (2015). source

      The Results section on distinct ciliary compartments describes the localization of PI(4)P and PI(4,5)P2, not PKA activation. Searches of our full-text copy for PKA, cAMP, AKAP, and the proposed mechanism found no passage addressing local cAMP production or PKA anchoring. The copy provides neither support for nor a contradiction of the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activated ciliary V2R seems to activate adenylyl cyclase, increasing local cAMP and activating a cation-selective channel to regulate intraciliary Ca2+ signals.

    “Upon activation, ciliary V2R seems to activate adenylyl cyclase, which increases local cAMP concentrations and activates a cation-selective channel to regulate intraciliary Ca+2 signals 162.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [162] Jin, X. et al. Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli. Cell. Mol. Life Sci. 71, 2165–2178 (2014). source

      The Results and Discussion describe ciliary calcium signaling through dopamine receptor DR5 and the CaV1.2 channel, not through V2R. Searches for V2R, vasopressin, adenylyl cyclase, and the proposed cAMP-dependent channel pathway found no passage addressing that mechanism in our copy. No page numbers are available for these passages. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activation of GPBAR1 on non-ciliated cholangiocytes induces co-localization with Gαs, increases cAMP signalling, inhibits ERK signalling, and increases proliferation.

    “Activation of GPBAR1 on non-ciliated cholangiocytes induced co-localization of GPBAR1 with Gαs, increased cAMP signalling, inhibited ERK signalling, and increased cellular proliferation 155”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [155] Schou, K. B., Pedersen, L. B. & Christensen, S. T. Ins and outs of GPCR signaling in primary cilia. EMBO Rep. 16, 1099–1113 (2015). source

      The Introduction (page unavailable) reports that TGR5 ligands increased cAMP levels and proliferation and inhibited ERK signaling in non-ciliated cholangiocytes. It does not report that activation induced co-localization of GPBAR1 (TGR5) with Gαs, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Cholangiocyte cilia are enriched for P2RY12 and GPBAR1/TGR5, as well as adenylyl cyclase, PKA, EPAC2, and AKAP150.

    “cholangiocyte cilia are enriched for two different GPCRs — purinergic receptor P2Y12 (P2RY12) 155 and G-protein coupled bile acid receptor 1 (GPBAR1, also known as TGR5) 157, 158, as well as the cAMP signalling proteins adenylyl cyclase, PKA, exchange protein directly activated by cAMP isoform 2 (EPAC2), and A-kinase anchoring protein (AKAP150) 155”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [155] Schou, K. B., Pedersen, L. B. & Christensen, S. T. Ins and outs of GPCR signaling in primary cilia. EMBO Rep. 16, 1099–1113 (2015). source

      The Introduction (page unavailable) says TGR5 is enriched in cholangiocyte cilia. It discusses adenylyl cyclase in neuronal cilia and PKA in other signaling contexts, but does not establish enrichment of P2RY12, adenylyl cyclase, PKA, EPAC2, or AKAP150 in cholangiocyte cilia (searched P2Y12, EPAC2, and AKAP150). (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [157] Masyuk, A. I. et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G725–G734 (2008). source
    • cites [158] Masyuk, T. V., Masyuk, A. I. & LaRusso, N. F. TGR5 in the cholangiociliopathies. Dig. Dis. 33, 420–425 (2015). source

  • May combine two claims.

    Premisecitation

    SUFU restrains GLI3 in the cytoplasm and promotes GLI3R processing in a cilia-independent step.

    “Another negative regulator of SHH signalling, Suppressor of FUSED (SUFU) restrains GLI3 in the cytoplasm and promotes GLI3R processing 123 in a cilia-independent step 124.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [123] Wang, B., Fallon, J. F. & Beachy, P. A. Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423–434 (2000). source

      The Results describe formation of the Gli3-83 repressor and suggest that Gli3 processing may depend on PKA activity. Searches for SUFU, cytoplasmic restraint, and a cilia-independent step found no passage in our copy addressing SUFU’s proposed role or the cilia qualifier. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [124] Mukhopadhyay, S. et al. The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell 152, 210–223 (2013). source

  • May combine two claims.

    Premisecitation

    Overexpressed NPHP2/inversin inhibits DVL1-mediated activation of WNT reporter constructs in mammalian cells and rescues secondary axis formation induced by Dsh or CK1μ in Xenopus laevis.

    “nephrocystin-2 (NPHP2, also known as inversin, which when overexpressed inhibits DVL1-mediated activation of WNT reporter constructs in mammalian cells and rescues secondary axis formation induced by overexpression of Dsh or CK1μ in Xenopus laevis 198.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [198] Marion, V. et al. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc. Natl Acad. Sci. USA 106, 1820–1825 (2009). source

      The passages on Wnt signaling and BBS10/BBS12 knockdown in differentiating preadipocytes do not address NPHP2/inversin overexpression. Searches for DVL1-mediated WNT reporter activation and secondary-axis formation in Xenopus found no passage addressing those experiments. Section and page labels were unavailable in our copy. (LLM, conf=0.77)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    NPY has an important role in the central regulation of food intake and energy expenditure.

    “NPY also has an important role in the central regulation of food intake and energy expenditure 181.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [181] Siljee, J. E. et al. Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nat. Genet. 50, 180–185 (2018). source

      The Main Text (page unavailable) discusses MC4R-expressing neurons, their ligands αMSH and AGRP, and regulation of feeding and energy homeostasis. Searches for “NPY” and “neuropeptide Y” found no passage in our copy addressing NPY’s role in food intake or energy expenditure. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Activated NPY2R accumulates at the ciliary tip and is released in ectosomes.

    “activated NPY2R accumulates at the ciliary tip and is released in extracellular vesicles called ectosomes 28”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Nager, A. R. et al. An actin network dispatches ciliary GPCRs into extracellular vesicles to modulate signaling. Cell 168, 252–263 (2017). source

  • May combine two claims.

    Premisecitation

    Deletion of BBS proteins causes SSTR3, melanin-concentrating hormone receptor 1, and NPY2R to fail to localize to neuronal cilia, while dopamine receptor 1 accumulates in neuronal cilia.

    “deletion of BBS proteins leads to failure of somatostatin receptor subtype 3 (SSTR3), melanin-concentrating hormone receptor 1 and neuropeptide Y (NPY) receptor subtype 2 (NPY2R) to localize to neuronal cilia, whereas, dopamine receptor 1 accumulates in neuronal cilia 73, 74, 168.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [73] Berbari, N. F., Lewis, J. S., Bishop, G. A., Askwith, C. C. & Mykytyn, K. Bardet-Biedl syndrome proteins are required for the localization of G protein-coupled receptors to primary cilia. Proc. Natl Acad. Sci. USA 105, 4242–4246 (2008). source

      The paper’s opening summary and Results report that neurons from Bbs2- or Bbs4-null mice lack ciliary Sstr3 and Mchr1. Our copy does not report NPY2R failing to localize or dopamine receptor 1 accumulating in neuronal cilia; searches for those receptors found no supporting passage. Page numbers were not available. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [74] Loktev, A. V. & Jackson, P. K. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep. 5, 1316–1329 (2013). source
    • cites [168] Green, J. A. et al. Recruitment of β-arrestin into neuronal cilia modulates somatostatin receptor subtype 3 ciliary localization. Mol. Cell. Biol. 36, 223–235 (2016). source

  • May combine two claims.

    Premisecitation

    Morpholino-induced depletion of NPHP2 in X. laevis and zebrafish disrupts convergent extension, which is rescued by overexpression of mouse NPHP2 or Diversin.

    “morpholino-induced depletion of NPHP2 in X. laevis and zebrafish disrupted convergent extension — a process that was rescued by overexpression of mouse NPHP2 or Diversin, respectively 198.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [198] Marion, V. et al. Transient ciliogenesis involving Bardet-Biedl syndrome proteins is a fundamental characteristic of adipogenic differentiation. Proc. Natl Acad. Sci. USA 106, 1820–1825 (2009). source

      The section “BBS10 and BBS12 Affect Ciliogenesis and Adipogenic Pathways” (page not provided) describes RNAi knockdown in human preadipocytes, not NPHP2 morpholino depletion in Xenopus or zebrafish. Searches for NPHP2, Diversin, convergent extension, and the claimed rescue found no passage addressing those experiments in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Depletion of RPGRIP1L in mouse embryos leads to ventricular septal defects associated with loss of localization of PDGFRα to primary cilia and reduced expression of the PDGFRα target gene Hifα in cardiac ventricular tissue.

    “depletion of the gene that encodes the ciliary TZ NPHP module component, RPGRIP1L, in mouse embryos leads to ventricular septal defects associated with loss of localization, which display cardiac ventricular septal defects 254 is associated with loss of localization of PDGFRα to primary cilia and reduced expression of the PDGFRα target gene, Hifα, in cardiac ventricular tissue 243.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [243] Noda, K., Kitami, M., Kitami, K., Kaku, M. & Komatsu, Y. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc. Natl Acad. Sci. USA 113, E2589–E2597 (2016). source

      The Results (Fig. 2B–H; page not available) report loss of ciliary PDGFRα localization in Ift20-deficient cranial osteoblasts. They do not report RPGRIP1L depletion, ventricular septal defects, or reduced Hifα expression in cardiac ventricular tissue; searches for those terms found no supporting passage. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Although IGF-IR is localized and activated at the plasma membrane, adipocyte differentiation requires activation of IGF-IR in the primary cilium in 3T3-L1 preadipocytes.

    “although IGF-IR is localized and activated at the plasma membrane, adipocyte differentiation, which is associated with transient ciliogenesis 197, 230, requires activation of IGF-IR in the primary cilium in cultures of 3T3-L1 preadipocytes 230”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [230] Kunova Bosakova, M. et al. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum. Mol. Genet. 27, 1093–1105 (2018). source

      The Results section on transient FGF signaling describes FGF2-induced ciliary elongation in NIH3T3 fibroblasts, not IGF-IR activation in 3T3-L1 preadipocytes. Searches for IGF-IR, adipocyte differentiation, and transient ciliogenesis found no passage in our copy addressing the attributed claim; page numbers were unavailable. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    PDGFRα is principally localized to primary cilia, although non-ciliary localizations have been reported for specific cell types.

    “PDGFRα is principally localized to primary cilia 225, 240–243, although non-ciliary localizations for this isoform have been reported for specific cell types 243–245.”
    Quote in the paperNot a substantial claim5 of 7 sources checked
    • cites [225] Ma, R. et al. PKD2 functions as an epidermal growth factor-activated plasma membrane channel. Mol. Cell. Biol. 25, 8285–8298 (2005). source

      The Results and Discussion passages (page not provided) describe EGFR and PKD2 in primary cilia, not PDGFRα. Searches for PDGFRα and non-ciliary localization yielded no passage addressing either part of the claim. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [240] Heldin, C.-H., Lennartsson, J. & Westermark, B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J. Intern. Med. 283, 16–44 (2018). source
    • cites [241] Schneider, L. et al. PDGFRαα signaling is regulated through the primary cilium in fibroblasts. Curr. Biol. 15, 1861–1866 (2005). source
    • cites [242] Vestergaard, M. L., Awan, A., Warzecha, C. B., Christensen, S. T. & Andersen, C. Y. in Human Embryonic Stem Cell Protocols (ed. Turksen, K.) 123–140 (Springer, NY, 2016).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [243] Noda, K., Kitami, M., Kitami, K., Kaku, M. & Komatsu, Y. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc. Natl Acad. Sci. USA 113, E2589–E2597 (2016). source

      The Results (page unavailable) show PDGFRα on primary cilia in control osteoblasts and on the cell surface of Ift20-mutant osteoblasts lacking cilia. This supports ciliary localization and a non-ciliary example, but the paper does not establish that PDGFRα is principally ciliary across cell types. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [244] Gerhardt, C., Lier, J. M., Kuschel, S. & Rüther, U. The ciliary protein Ftm is required for ventricular wall and septal development. PLOS ONE 8, e57545 (2013). source

      The Introduction says PDGFRα localizes to cilia, and the Results report it along ventricular cilia in E11.5 mouse hearts (page numbers unavailable). The paper does not establish that its localization is principally ciliary or report non-ciliary localization in specific cell types; failure to detect it at atrial cilia does not establish where it is instead. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [245] Kopinke, D., Roberson, E. C. & Reiter, J. F. Ciliary Hedgehog signaling restricts injury-induced adipogenesis. Cell 170, 340–351 (2017). source

      The Results section, “FAPs are dynamically ciliated during muscle regeneration” (page unavailable), says that PDGFRα-expressing FAPs are frequently ciliated. That describes the cells, not where PDGFRα itself is located. Searches for ciliary and non-ciliary PDGFRα localization found no passage addressing either part of the claim. (LLM, conf=0.75)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Depletion of BBS4 in cultured cells reduces proteasomal activity and leads to accumulation of cytoplasmic and nuclear β-catenin.

    “depletion of BBS4 in cultured cells (which results in both canonical and WNT–PCP defects in zebrafish) reduces proteasomal activity and leads to an accumulation of cytoplasmic and nuclear β-catenin 216”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [216] Gerhardt, C. et al. The transition zone protein Rpgrip1l regulates proteasomal activity at the primary cilium. J. Cell Biol. 210, 1027 (2015). source

      The Discussion reports that Bbs4 is essential for proteasomal degradation or processing, supporting the proteasomal part of the claim. The Results report increased phosphorylated β-catenin at the ciliary base after Rpgrip1l loss, not cytoplasmic and nuclear β-catenin accumulation after BBS4 depletion. The cited passages also do not establish the parenthetical zebrafish defects. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Primary cilia are redundant for both branches of WNT signalling.

    “demonstrating that primary cilia are redundant for both branches of WNT signalling 203.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [203] Vuong, L. T., Mukhopadhyay, B. & Choi, K.-W. Kinesin-II recruits Armadillo and Dishevelled for Wingless signaling in Drosophila. Development 141, 3222–3232 (2014). source

      The Discussion (page unavailable) reports that studies suggest cilia have no role in Wnt signalling during early development. That narrower, hedged statement does not establish that primary cilia are redundant for both branches of WNT signalling across contexts; the same passage says their role has not been clearly defined. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Defects in glucose handling in these models are linked to defects in insulin-mediated activation of the PI3K-AKT pathway in β-cells, which relies on ciliary recruitment of activated IR subtype A (IR-A), which controls insulin production.

    “These defects in glucose handling are linked to defects in insulin-mediated activation of the PI3K–AKT pathway in β-cells, which relies on ciliary recruitment of activated IR subtype A (IR-A), which controls the production of insulin in these cells 235, 238.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [235] Wang, H. et al. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling. J. Cell Sci. 128, 100–108 (2015). source
    • cites [238] Song, D. K., Choi, J. H. & Kim, M.-S. Primary cilia as a signaling platform for control of energy metabolism. Diabetes Metab. J. 42, 117–127 (2018). source

      The section 'Cilia-Related Signaling in the Control of Glucose Metabolism' discusses cilia-dependent glucose uptake through SMO and AMPK in fibroblasts, muscle, and brown adipocytes. Searches for PI3K–AKT, IR-A, and β-cell insulin production found no passage linking glucose-handling defects to the β-cell mechanism claimed here. The reported glucose-uptake pathway is a different setting, not a contradiction of the claim. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In fibroblasts, ciliary PDGFRα signaling activates the PI3K-AKT and MEK1/2-ERK1/2-RSK pathways to control directional cell migration, achieved by targeting NHE1 to the leading edge of migrating cells.

    “In fibroblasts, ciliary PDGFRα signalling activates the PI3K–AKT and MEK1/2–ERK1/2–RSK pathways to control directional cell migration, which is achieved by targeting the Na+/H+ exchanger 1, NHE1, to the leading edge of the migrating cells, which project their cilium towards the leading edge and parallel to the path of motility 240, 247–249.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [240] Heldin, C.-H., Lennartsson, J. & Westermark, B. Involvement of platelet-derived growth factor ligands and receptors in tumorigenesis. J. Intern. Med. 283, 16–44 (2018). source
    • cites [247] Nielsen, B. S. et al. PDGFRβ and oncogenic mutant PDGFRα D842V promote disassembly of primary cilia through a PLCγ- and AURKA-dependent mechanism. J. Cell Sci. 128, 3543–3549 (2015). source
    • cites [248] Schneider, L. et al. Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell. Physiol. Biochem. 25, 279–292 (2010). source

      The Results (‘PDGF-AA signals through Akt at the ciliary base’) show PDGF-AA-dependent PDGFRα and Akt activation, and the Introduction reports that migrating fibroblasts orient their cilia toward the leading edge. The Discussion (‘Conclusions and perspectives’) describes MEK1/2–ERK1/2 signaling and its connection through RSK to NHE1, but treats a link from ciliary signaling to leading-edge NHE1 events as a possibility or hypothesis. It does not establish that ciliary PDGFRα controls migration by targeting NHE1 to the leading edge. No page numbers are provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [249] Schneider, L. et al. The Na+/H+ exchanger NHE1 is required for directional migration stimulated via PDGFR-α in the primary cilium. J. Cell Biol. 185, 163–176 (2009). source

      The Introduction and Discussion support ciliary PDGFR-α signaling and a role for NHE1 activity in directional fibroblast migration; the Discussion also reports ERK1/2 and PI3K–Akt activation. But it describes p90RSK as a possible link to NHE1, and says increased NHE1 targeting to the leading-edge membrane after PDGF-AA was not convincingly observed. The claim presents those proposed mechanisms as established. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Defects in primary cilia formation by depletion of IFT-B proteins such as IFT88 and IFT172 block PDGFRα activation, rendering cells unable to respond and move towards a PDGF-AA gradient.

    “Consequently, defects in the formation of primary cilia by depletion of IFT-B proteins such as IFT88 and IFT172 block PDGFRα activation 247, 250, rendering the cells unable to respond and move towards a gradient of PDGF-AA 247.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [247] Nielsen, B. S. et al. PDGFRβ and oncogenic mutant PDGFRα D842V promote disassembly of primary cilia through a PLCγ- and AURKA-dependent mechanism. J. Cell Sci. 128, 3543–3549 (2015). source
    • cites [250] Clement, D. L. et al. PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2–ERK1/2–p90RSK and AKT signaling pathways. J. Cell Sci. 126, 953–965 (2013). source

      The Cell cultures section identifies Tg737 as encoding IFT88 and says mutant fibroblasts form no or stunted cilia. The ciliary PDGFRαα signaling section says these cells cannot activate the receptor in response to PDGF-AA and lack chemotaxis toward a PDGF-AA gradient. Our copy does not establish the same result for depletion of IFT172. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NPHP4 stabilizes JADE1 and promotes its nuclear translocation.

    “NPHP4 was reported to stabilize the E3 PHD finger domain E3 ubiquitin ligase JADE1 and promote its nuclear translocation 213.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [213] Patnaik, S. R. et al. RPGR protein complex regulates proteasome activity and mediates store-operated calcium entry. Oncotarget 9, 23183–23197 (2018). source

      The Results section on DVL proteins discusses NPHP4 in relation to DVL2 and DVL3 degradation, not JADE1. Searches for JADE1 and for the claimed stabilization and nuclear translocation found no passage addressing that relationship in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NPHP2 promotes WNT-PCP signalling by facilitating fzd8-mediated recruitment of Dvl to the membrane, and proximal pronephros extension is disrupted by NPHP2 depletion, while normal WNT-β-catenin signalling is unaffected.

    “NPHP2 promotes WNT–PCP signalling by facilitating fzd8-mediated recruitment of Dvl to the membrane, and that proximal pronephros extension is disrupted by morpholino-mediated depletion of NPHP2 199, although normal WNT–β-catenin signalling was unaffected in this study.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [199] Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543 (2005). source

      The indexed text (section labeled Abstract; page unavailable) supports an involvement of inversin/NPHP2 in noncanonical Wnt signaling and reports that morpholino depletion causes pronephric duct cysts. It does not report fzd8-mediated recruitment of Dvl or disrupted proximal pronephros extension. Contrary to the claim that canonical Wnt–β-catenin signaling was unaffected, it reports increased β-catenin–TCF target-gene expression after inversin depletion. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    RAB11, responsible for endosomal recycling of TGFβ receptors, is recruited to the cilium in a process mediated by CEP128; loss of CEP128 leads to impaired phosphorylation of R-SMADs, which in zebrafish is associated with defective organ development.

    “RAB11 285, which is responsible for endosomal recycling of TGFβ receptors 286, is recruited to the cilium in a process that is mediated by the subdistal appendage protein, CEP128 287. Consequently, loss of CEP128 leads to impaired phosphorylation of R-SMADs, which in zebrafish is associated with defective organ development 287.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [285] Mitchell, H., Choudhury, A., Pagano, R. E. & Leof, E. B. Ligand-dependent and -independent transforming growth factor-β receptor recycling regulated by clathrin-mediated endocytosis and Rab11. Mol. Biol. Cell 15, 4166–4178 (2004). source

      Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [287] Miyazawa, K. & Miyazono, K. Regulation of TGF-β family signaling by inhibitory smads. Cold Spring Harb. Perspect. Biol. 9, a022095 (2017). source

  • May combine two claims.

    Premisecitation

    Endothelial primary cilia function as flow sensors in the vasculature and contribute to blood-brain barrier integrity, counteract endothelial-to-mesenchymal transition in a process associated with reduced canonical TGFβ signaling in the endocardial cushion area, and cooperate with BMP signaling to stabilize vessel connections in the developing mouse retina.

    “Further, endothelial primary cilia, which function as flow sensors in the vasculature and contribute to blood–brain barrier integrity 276–279, counteract endothelial-to-mesenchymal transition in a process that is associated with reduced canonical TGFβ signalling in the endocardial cushion area 280, whereas endothelial primary cilia cooperate with BMP signalling to stabilize vessel connections in”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [276] Goetz & Jacky, G. et al. Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Rep. 6, 799–808 (2014). source
    • cites [277] Kallakuri, S. et al. Endothelial cilia are essential for developmental vascular integrity in zebrafish. J. Am. Soc. Nephrol. 26, 864–875 (2015). source

      Split into 3 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [278] Hierck, B. P. et al. Primary cilia sensitize endothelial cells for fluid shear stress. Dev. Dyn. 237, 725–735 (2008). source
    • cites [279] Egorova, A. D. et al. Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ. Res. 108, 1093–1101 (2011). source

      Split into 3 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [280] Vion, A.-C. et al. Primary cilia sensitize endothelial cells to BMP and prevent excessive vascular regression. J. Cell Biol. 217, 1651–1665 (2018). source

      Split into 3 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [281] Kawasaki, M. et al. TGF-β suppresses Ift88 expression in chondrocytic ATDC5 cells. J. Cell. Physiol. 230, 2788–2795 (2015). source

  • May combine two claims.

    Interpretationreasoning

    These results suggest a biochemical and functional relationship between IFT20 and CBL proteins in ciliary receptor sorting and modulation of PDGFRα signaling, which when defective underlies tumorigenic signaling in various tissues.

    “These results suggest the existence of a biochemical and functional relationship between IFT20 and CBL proteins in ciliary receptor sorting and modulation of PDGFRα signalling, which when defective underlies tumorigenic signalling in various tissues 239.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [239] Leibiger, B. et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol. Cell 7, 559–570 (2001). source

      The Conclusion (page not provided) discusses selective signaling through insulin receptor isoforms IR-A and IR-B, not ciliary receptor sorting. Searches for IFT20, CBL, PDGFRα and tumorigenic signaling found no passage in our copy addressing the attributed relationship. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The mechanisms that control the balanced output of ciliary signaling described in this Review might also apply to other pathways such as Hippo and Notch signaling pathways or those regulated by receptors of extracellular matrix molecules, which also have been linked to primary cilia in various cell types and tissues.

    “The mechanisms that control the balanced output of ciliary signalling described in this Review might also apply to other pathways such as Hippo and Notch signalling pathways or those regulated by receptors of extracellular matrix molecules, which also have been linked to primary cilia in various cell types and tissues 23, 291, 292.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [23] Morthorst, S. K., Christensen, S. T. & Pedersen, L. B. Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins. FEBS J. 285, 4535–4564 (2018). source

      The Introduction links Notch and Hippo signalling to primary cilia, and the TGF-β/BMP signalling section describes ciliary control of balanced signalling output. The paper does not substantiate the additional claim that pathways regulated by receptors of extracellular-matrix molecules are linked to primary cilia in various cell types and tissues. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [291] Seeger-Nukpezah, T. & Golemis, E. A. The extracellular matrix and ciliary signaling. Curr. Opin. Cell Biol. 24, 652–661 (2012). source
    • cites [292] Wood, C. R. & Rosenbaum, J. L. Ciliary ectosomes: transmissions from the cell’s antenna. Trends Cell Biol. 25, 276–285 (2015). source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SMURF1 negatively regulates phosphorylation of SMAD1/5/8 at primary cilia to control cell-type specification during in vivo heart development, which in Smurf1−/− mouse embryos is associated with delayed outflow tract septation.

    “Finally, the E3 ubiquitin ligase SMURF1 negatively regulates phosphorylation of SMAD1/5/8 at primary cilia to control cell-type specification during in vivo heart development, which in Smurf1−/− mouse embryos is associated with delayed outflow tract septation 273.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [273] Gencer, S. et al. TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci. Signal. 10, eaam7464 (2017). source

      The Results section on ciliary trafficking addresses CerS4, Smad7, TGF-β receptors, and cancer-cell migration, not SMURF1 regulation of SMAD1/5/8 during heart development. Searches for SMURF1, Smurf1−/− embryos, and outflow tract septation found no passage addressing the claim. The available passages have no page numbers. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisenone given

    Specific receptors and signal transduction proteins localize to primary cilia in a cell type-dependent manner, and the ciliary set of these proteins can change over time to adapt to developmental and homeostatic cues.

    “Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    The ciliary membrane is continuous with the plasma membrane but has a unique lipid and receptor composition that allows the cilium to detect extracellular changes and convey signals to regulate cellular, developmental and physiological processes.

    “The cilium is enclosed by a membrane that is continuous with the plasma membrane but has a unique lipid and receptor composition that enables the cilium to detect changes in the extracellular environment and convey signalling information to the cell to regulate diverse cellular, developmental and physiological processes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    The axoneme of a primary cilium has nine outer microtubule doublets (9+0), while a motile cilium has nine outer doublets around two central singlets (9+2).

    “The axoneme of a primary cilium contains a ring of nine outer microtubule doublets (known as a 9+0 axoneme), whereas the axoneme of a motile cilium has nine outer microtubule doublets around two central microtubule singlets (called a 9+2 axoneme).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Primary cilia are solitary microtubule-based organelles that extend from the surface of most vertebrate cell types and detect and transmit extracellular signals to regulate development and tissue homeostasis.

    “Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Satir, P. & Christensen, S. T. Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69, 377–400 (2007). source

  • May combine two claims.

    Premisecitation

    The primary cilium is a microtubule-based, non-motile organelle that extends as a solitary unit from the basal body, which is derived from the centrosomal mother centriole in most human cell types.

    “The primary cilium is a microtubule-based, non-motile organelle that extends as a solitary unit from the basal body (derived from the centrosomal mother centriole of most cell types in the human body 1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Satir, P. & Christensen, S. T. Overview of structure and function of mammalian cilia. Annu. Rev. Physiol. 69, 377–400 (2007). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The basal body is a modified centriole with specialized distal structures that regulate ciliary biogenesis and function.

    “The basal body is a modified centriole that contains specialized structures at its distal end that regulate critical aspects of ciliary biogenesis and function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The IFT system was discovered in 1993 through observation of continuous particle movement between the flagellar membrane and axonemal outer doublet microtubules from base to tip and back in Chlamydomonas reinhardtii flagella.

    “The IFT system was discovered in 1993 following the observation of a continuous movement of particles, sandwiched between the flagellar membrane and axonemal outer doublet microtubules, from the flagellar base to tip (anterograde IFT) and back (retrograde IFT) in Chlamydomonas reinhardtii flagella32.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Kozminski, K. G., Johnson, K. A., Forscher, P. & Rosenbaum, J. L. A motility in the eukaryotic flagellum unrelated to flagellar beating. Proc. Natl Acad. Sci. USA 90, 5519–5523 (1993). source

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that SHH-mediated activation and removal of PTCH1 from cilia might increase the availability of endogenous SMO ligands, most likely cholesterol or cholesterol derivatives, in the ciliary membrane, thereby leading to activation of SMO in cilia.

    “These findings suggest that SHH-mediated activation and removal of PTCH1 from cilia might increase the availability of endogenous SMO ligands — most likely cholesterol or cholesterol derivatives — in the ciliary membrane, thereby leading to activation of SMO in cilia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Activation of the SHH pathway through GLI transcriptional activator formation and basal repression through GLI transcriptional repressor are both dependent on the primary cilium.

    “Activation of the SHH pathway by formation of the GLI transcriptional activator (GLIA) and basal repression of the SHH pathway by GLI transcriptional repressor (GLIR) are both dependent on the primary cilium 97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003). source

  • May combine two claims.

    Premisecitation

    Prior work in C. elegans demonstrated that homologs of human autosomal dominant PKD1 and PKD2 gene products, PC1 and PC2, localize to neuronal sensory cilia and regulate male mating behaviour.

    “and was supported by prior work in C. elegans demonstrating that homologs of the human autosomal dominant (AD) PKD1 and PKD2 gene products, the transmembrane proteins polycystin (PC) 1 and PC2, localize to neuronal sensory cilia and regulate male mating behaviour 81.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Barr, M. M. & Sternberg, P. W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401, 386–389 (1999). source

  • May combine two claims.

    Premisenone given

    SHH secretion from distinct regions, such as Purkinje neurons in the postnatal cerebellum and the zone of polarizing activity in limb buds, patterns these tissues, and each of these tissues expresses low or no SHH at distinct stages of development.

    “Although SHH secretion from distinct regions, such as the purkinje neurons in the postnatal cerebellum and the zone of polarizing activity in limb buds, patterns these tissues, each of these tissues expresses low or no SHH at distinct stages of development.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    D5-induced cilia lengthening might increase sensitivity to fluid flow and inhibit cystogenesis.

    “which might increase sensitivity to fluid flow 161 and inhibit cystogenesis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [161] Cramer, M. T. & Guay-Woodford, L. M. Cystic kidney disease: a primer. Adv. Chronic Kidney Dis. 22, 297–305 (2015). source

  • May combine two claims.

    Interpretationcitation

    Active repression of the HH pathway by GPR161 regulates tissue architecture, whereas pathway de-repression contributes to disease pathogenesis.

    “Thus, active repression of HH pathway by GPR161 regulates tissue architecture, whereas pathway de-repression contributes to disease pathogenesis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Direct coupling of the type I PKA regulatory subunit alpha to PKA in the ciliary compartment might enhance GPR161 ability to activate PKA via constitutive cAMP signalling.

    “direct coupling of this subunit to PKA in this compartment might enhance the ability of GPR161 to activate PKA via constitutive cAMP signalling.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Activation of D5 increases calcium levels in the cilium and causes an actin-mediated increase in cilia length.

    “Activation of D5 caused an increase in calcium levels in the cilium along with an actin-mediated increase in cilia length”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Cramer, M. T. & Guay-Woodford, L. M. Cystic kidney disease: a primer. Adv. Chronic Kidney Dis. 22, 297–305 (2015). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Ciliary GPCR signals might be transmitted between cells.

    “raising the fascinating possibility that ciliary GPCR signals might be transmitted between cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Interneurons lacking ARL13B show disrupted ciliary calcium dynamics and reduced ciliary localization of SSTR3.

    “Interneurons lacking ARL13B also show disrupted ciliary calcium dynamics and a dramatic reduction in ciliary localization of SSTR3 171.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012). source

  • May combine two claims.

    Premisecitation

    Disruption of cilia on trophoblast cells ameliorates EG-VEGF-induced ERK1/2 activation, MMP upregulation, and cell invasion.

    “Disruption of cilia on trophoblast cells ameliorates EG-VEGF-induced activation of ERK1/2, MMP upregulatoin, and cell invasion 164.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Raychowdhury, M. K. et al. Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells. Am. J. Physiol. Renal Physiol. 296, F87–F97 (2009). source

  • May combine two claims.

    Premisecitation

    BBS mutant mice lacking NPY2R-positive cilia are obese and do not respond to NPY2R ligand.

    “BBS mutant mice that lack NPY2R-positive cilia are obese and do not respond to NPY2R ligand 74”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Loktev, A. V. & Jackson, P. K. Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia. Cell Rep. 5, 1316–1329 (2013). source

  • May combine two claims.

    Premisecitation

    EG-VEGF treatment of trophoblast cells activates ERK1/2 signalling, upregulates MMPs, and facilitates cell invasion.

    “Treatment of trophoblast cells with EG-VEGF activates ERK1/2 signalling to induce upregulation of matrix metalloproteinases (MMPs) and facilitate cell invasion 164.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [164] Raychowdhury, M. K. et al. Vasopressin receptor-mediated functional signaling pathway in primary cilia of renal epithelial cells. Am. J. Physiol. Renal Physiol. 296, F87–F97 (2009). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mutations in MC4R are the most common cause of monogenic obesity in humans, underlying up to 6% of early-onset or severe adult obesity.

    “mutations in MC4R are the most common cause of monogenic obesity in humans, underlying up to 6% of early-onset or severe cases of adult obesity 179.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [179] Davenport, J. R. et al. Disruption of intraflagellar transport in adult mice leads to obesity and slow-onset cystic kidney disease. Curr. Biol. 17, 1586–1594 (2007). source

  • May combine two claims.

    Premisecitation

    Loss of ARL13B in interneurons reduces dendritic and axonal complexity, disrupts synaptic connectivity, and causes functional deficits in synaptic activity.

    “loss of ARL13B in interneurons results in reduced dendritic and axonal complexity, disrupted synaptic connectivity, and functional deficits in synaptic activity 171.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012). source

  • May combine two claims.

    Premisecitation

    Expression of SSTR3 in ARL13B-deficient interneuronal cilia rescues morphological and synaptic connectivity defects, whereas non-ciliary ARL13B does not.

    “expression of SSTR3 in ARL13B-deficient interneuronal cilia rescues the morphological and synaptic connectivity defects, whereas expression of a non-ciliary form of ARL13B with normal GTPase activity does not rescue the developmental defects in ARL13B-deficient interneurons 171”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Marin, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012). source

  • May combine two claims.

    Premisecitation

    Multiple lines of evidence from gene knockout or knockdown studies suggest roles for cilia in regulating WNT signalling, but the literature is controversial.

    “although multiple lines of evidence from gene knockout or knockdown studies have suggested roles for cilia in regulating WNT signalling, the literature in this field is controversial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    JADE1 is a negative regulator of WNT-beta-catenin signalling that ubiquitinates cytoplasmic and nuclear beta-catenin irrespective of phosphorylation, promoting proteasomal degradation.

    “JADE1 is a negative regulator of WNT–β-catenin signalling that ubiquitinates cytoplasmic and nuclear β-catenin irrespective of its phosphorylation status, thereby promoting its proteasomal degradation 214.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Borgal, L. et al. The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate β-catenin signaling. J. Biol. Chem. 287, 25370–25380 (2012). source

  • May combine two claims.

    Premisecitation

    NPHP3 and NPHP4 restrain DVL-mediated WNT-beta-catenin activation in cell culture, and their depletion induces WNT-PCP defects in vivo.

    “Similarly to NPHP2, NPHP3 and NPHP4 restrain DVL-mediated WNT–β-catenin activation in cell culture, and when depleted, induce WNT–PCP defects in vivo (PMID 18371931 and PMID 21498478).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites PMID 18371931 and PMID 21498478

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Interpretationreasoning

    NPHP4 negatively regulates beta-catenin levels through JADE1 in addition to its negative effect on DVL.

    “Thus, NPHP4, in addition to its negative effect on DVL, also negatively regulates β-catenin levels through JADE1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Young Bbs4-knockout mice demonstrate impaired glucose handling before the onset of obesity, and ciliary dysfunction induced by knockdown of BBS4 or OFD-1 attenuates first-phase insulin secretion in pancreatic islet cells independent of glucose metabolism.

    “Young Bbs4-knockout mice demonstrate impaired glucose handling before the onset of obesity, and ciliary dysfunction induced by knockdown of BBS4 or oral-facial-digital syndrome 1 protein (OFD-1) attenuates first-phase insulin secretion in pancreatic islet cells independent of glucose metabolism 235.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Wang, H. et al. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling. J. Cell Sci. 128, 100–108 (2015). source

  • May combine two claims.

    Premisecitation

    IFT20 stabilizes the RING-finger domain family of CBL E3 ubiquitin ligases, c-CBL and CBL-b, which are tumor suppressor proteins that target active PDGFRs for internalization and degradation.

    “IFT20 appears to have a central role in this context by stabilizing the RING-finger domain family of CBL E3 ubiquitin ligases, c-CBL and CBL-b, which are tumour suppressor proteins that target active PDGFRs for internalization and degradation 256”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [256] Koefoed, K., Veland, I. R., Pedersen, L. B., Larsen, L. A. & Christensen, S. T. Cilia and coordination of signaling networks during heart development. Organogenesis 10, 108–125 (2014). source

  • May combine two claims.

    Interpretationreasoning

    Many RTKs can also localize outside the primary cilium, indicating that cilia could constitute a specialized site for organizing signaling events that might affect cellular processes differently from extra-ciliary sites.

    “However, many of these receptors can also localize outside the primary cilium, indicating that cilia could constitute a specialized site for organizing cellular signalling events that might affect cellular processes differently from those organized at extra-ciliary sites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Primary cilia in islet β-cells are implicated in insulin production, and dysfunctional cilia in these cells contribute to susceptibility to metabolic diseases such as type 2 diabetes mellitus.

    “Evidence also suggests that primary cilia in islet β-cells of the pancreas are implicated in insulin production and that dysfunctional cilia in these cells contribute to susceptibility to metabolic diseases such type 2 diabetes mellitus (T2DM) 235”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [235] Wang, H. et al. Hsp90α forms a stable complex at the cilium neck for the interaction of signalling molecules in IGF-1 receptor signalling. J. Cell Sci. 128, 100–108 (2015). source

  • May combine two claims.

    Interpretationcitation

    The observation that RPGRIP1L depletion leads to ventricular septal defects and loss of PDGFRα localization supports the general concept that dysfunctional cardiac cilia cause congenital heart defects.

    “The latter observation supports the general concept that that dysfunctional cardiac cilia cause congenital heart defects 255.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [255] Vierkotten, J., Dildrop, R., Peters, T., Wang, B. & Rüther, U. Ftm is a novel basal body protein of cilia involved in Shh signalling. Development 134, 2569–2577 (2007). source

  • May combine two claims.

    Premisecitation

    TGFβ signaling is associated with activation of ERK1/2 at the ciliary base, but TGFβ1-induced phosphorylation of this MAP kinase seemed to occur independently of clathrin-mediated endocytosis.

    “Similarly, TGFβ signalling was associated with activation of ERK1/2 at the ciliary base, but in contrast to SMAD2/3, TGFβ1-induced phosphorylation of this MAP kinase seemed to occur independently of clathrin-mediated endocytosis 268.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [268] Bakkebø, M. et al. SARA is dispensable for functional TGF-β signaling. FEBS Lett. 586, 3367–3372 (2012). source

  • May combine two claims.

    Interpretationnone given

    While some pathways are considered bona fide ciliary pathways, such as canonical HH signaling, other pathways might be only partially associated with cilia and probably act in cell type-specific and developmentally dedicated contexts.

    “In this regard it is important to recognize that while some pathways are considered to be bona fide ciliary pathways, such as canonical HH signalling, other pathways might be only partially associated with cilia and probably act in cell type-specific and developmentally dedicated contexts.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Primary cilia are highly dynamic organelles whose configuration is tightly coupled to the differentiation state and microenvironment of the cell, and this flexibility might explain how cells are able to receive and convert signaling inputs in different cellular, developmental, and homeostatic settings.

    “In this context, it is important to recognize that primary cilia are highly dynamic organelles whose configuration is tightly coupled to the differentiation state and microenvironment of the cell, and that this flexibility of the cilium might explain how cells are able to receive and convert signalling inputs in different cellular, developmental and homeostatic settings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    These findings indicate that the primary cilium uses diverse mechanisms to fine-tune the output of canonical and non-canonical TGFβ signaling to control varied cellular responses, which could be relevant for heart development.

    “These findings indicate that the primary cilium uses diverse mechanisms to fine-tune the output of canonical and non-canonical TGFβ signalling to control varied cellular responses, which could be relevant for processes such as those related to heart development”
    Quote in the paperSubstantial claim
92 of 92

  • The paper relies on this without support.

    Cilia cannot synthesize proteins.

    “Cilia are unable to synthesize proteins; therefore, cilia-associated transport pathways also function during cilium biogenesis and maintenance by delivering the building blocks required for ciliary axoneme and”

  • The paper relies on this without support.

    Proper functioning of PC1 and PC2 requires their appropriate targeting to the ciliary compartment.

    “It is generally accepted that proper functioning of PC1 and PC2 relies on their appropriate targeting to the ciliary compartment, but the precise mechanism by which the polycystins function at cilia to prevent cyst formation and control left-right patterning during development is a matter of intense”

  • The paper relies on this without support.

    Findings from cultured cells and mouse models can be extrapolated to human development and disease.

    “Young Bbs4-knockout mice demonstrate impaired glucose handling before the onset of obesity, and ciliary dysfunction induced by knockdown of BBS4 or oral-facial-digital syndrome 1 protein (OFD-1) attenuates first-phase insulin secretion in pancreatic islet cells independent of glucose metabolism 235.”

  • The paper relies on this without support.

    Primary cilia are present on most cell types, but not all cell types in a given tissue or organ will be ciliated.

    “Cilia are present on most cell types, but not all cell types in a given tissue or organ will be ciliated.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The dynamic composition of ciliary proteins endows primary cilia with the capacity to transduce a multitude of signal inputs through an intricate signalling network.

    “The dynamic composition of ciliary proteins endows primary cilia with the capacity to transduce a multitude of signal inputs through an intricate signalling network.This mechanism enables primary cilia to process information in both temporal and spatial dimensions, integrating complex cellular cues with high precision (Anvarian et al. 2019).”

    From Changes of the Primary Cilia in Alzheimer's Disease Pathogenesis (2025) · cites this paper as Anvarian et al. 2019

  • The primary cilium enables extracellular signalling through a variety of ion channels and signalling receptors.

    “The axoneme of the primary cilium protrudes from the cell surface, which enables extracellular signalling through a variety of ion channels and signalling receptors (Wheway et al. 2018; Anvarian et al. 2019).”

    From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Anvarian et al. 2019

  • PKD is one of the most common ciliopathies and these disorders are associated with decreased autophagy.

    “PKD is one of the most common ciliopathies and these disorders are associated with decreased autophagy174.”

    From Autophagy in kidney homeostasis and disease (2020) · cites this paper as [174]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. Crudden, C. et al. in International Review of Cell and Molecular Biology Vol. 339. (ed. Shukla, A. K.) 1–40 (Academic Press, 2018).
  2. Vestergaard, M. L., Awan, A., Warzecha, C. B., Christensen, S. T. & Andersen, C. Y. in Human Embryonic Stem Cell Protocols (ed. Turksen, K.) 123–140 (Springer, NY, 2016).

Cited by

Sorted by citations

Related

Authors
Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B., & Christensen, S. T.
Affiliations
  • University of Copenhagen (DK)
  • The Ohio State University (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Christensen, Søren Tvorup
ORCID
Venue
Nature Reviews Nephrology
Publisher
Springer Science and Business Media LLC
Published
2019-02-07
Volume
15
Issue
4
Pages
199-219
ISSN
  • 1745-8323 (ISSN-L)
  • 1759-5061
  • 1759-507X
DOI
10.1038/s41581-019-0116-9
PMC
PMC6426138
OpenAlex
W2913985590
Semantic Scholar
9770a2e80c962ddd3ea2d42eb7ba6e6b794d59d8
Cited by
845
References
307
Citations by year
2026: 86 · 2025: 165 · 2024: 127 · 2023: 135 · 2022: 122 · 2021: 112 · 2020: 72 · 2019: 24
FWCI
10.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Nephrology (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Lundbeckfonden (R54-2010-5375)
  • Novo Nordisk Fonden (NNF15OC0016886, NNF18OC0053024, NNF14OC0011535)
  • National Institutes of Health (R01‐grant)
  • National Institute of Mental Health (R21MH107021)
  • National Institute of General Medical Sciences (R01GM113023)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
Keywords
primary cilia, Hedgehog signaling, ciliopathies, G protein-coupled receptor signaling, Wnt signaling, receptor tyrosine kinase signaling, signal transduction, tissue homeostasis, developmental disorders
MeSH terms
Cell Differentiation, Cell Movement, Cilia, Ciliary Motility Disorders, Homeostasis, Humans, Signal Transduction, Organogenesis, Hedgehog Proteins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review