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Cited by 239Down syndrome and intellectual disability researchNeurogenesis and neuroplasticity mechanismsGenetics and Neurodevelopmental Disorders

Down Syndrome Developmental Brain Transcriptome Reveals Defective Oligodendrocyte Differentiation and Myelination

Open access
Olmos-Serrano, Jose Luis, Kang, Hyo Jung, Tyler, William A., Silbereis, John C., Cheng, Feng, Zhu, Ying, Pletikos, Mihovil, Jankovic-Rapan, Lucija +9 more·2016·Neuron
DOI 10.1016/j.neuron.2016.01.042PMC PMC4795969
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Abstract

Trisomy 21, or Down syndrome (DS), is the most common genetic cause of developmental delay and intellectual disability. To gain insight into the underlying molecular and cellular pathogenesis, we conducted a multi-region transcriptome analysis of DS and euploid control brains spanning from mid-fetal development to adulthood. We found genome-wide alterations in the expression of a large number of genes, many of which exhibited temporal and spatial specificity and were associated with distinct biological processes. In particular, we uncovered co-dysregulation of genes associated with oligodendrocyte differentiation and myelination that were validated via cross-species comparison to Ts65Dn trisomy mice. Furthermore, we show that hypomyelination present in Ts65Dn mice is in part due to cell-autonomous effects of trisomy on oligodendrocyte differentiation and results in slower neocortical action potential transmission. Together, these results identify defects in white matter development and function in DS, and they provide a transcriptional framework for further investigating DS neuropathogenesis.

AI snapshot

Written from the paper’s full text.

TL;DR

Multi-region developmental transcriptome profiling of Down syndrome and euploid brains revealed widespread spatiotemporal gene dysregulation, including downregulation of oligodendrocyte differentiation and myelination gene networks. Cross-species validation in Ts65Dn mice showed hypomyelination, impaired oligodendrocyte maturation, fewer nodes of Ranvier, and slower myelinated action potential conduction.

Key findings

  • Of 17,557 mRNA genes profiled, 842 (4.8%) in dorsal frontal cortex (DFC) and 571 (3.25%) in cerebellar cortex (CBC) were significantly differentially expressed (DEX) across all periods (FDR = 0.1). HSA21 DEX genes were enriched (19.5% DFC, 13.9% CBC), but most DEX genes were non-HSA21 (1,337 vs 76 on HSA21); all HSA21 DEX genes were up-regulated, while non-HSA21 DEX genes were mixed (DFC: 47.7% up, 52.3% down; CBC: 45.2% up, 54.8% down).
  • WGCNA identified 60 modules; module M43 was enriched for regulation of action potential (BHA p=1.7×10⁻²) and axon ensheathment (BHA p=3.7×10⁻²) and was down-regulated in DS neocortex and hippocampus. Of 121 mouse homologs in M43, 67 had high expression (FPKM > 20), and 82.1% (55/67) were highly expressed by oligodendrocyte lineage cells; 8 of the top 10 hub genes were primarily expressed by mature oligodendrocytes.
  • Human DS DFC showed lower MAG and MBP transcript/protein levels, reduced myelinated fiber density, and lack of grid-like myelinated fiber orientation. Ts65Dn mice showed reduced MAG/MBP at P30 and CNP at P60, fewer small-bore myelinated axons (0–0.5 μm²; p=0.046), thinner myelin sheaths (g-ratio p<0.011), fewer nodes of Ranvier (p<0.005), and slower myelinated axon conduction (N1 p=0.04, n=10) with no difference in unmyelinated axons (N2 p=0.4, n=11).
  • Human DS DFC showed increased oligodendrocyte precursor cell-related gene expression until periods 12–14 and decreased myelinating oligodendrocyte genes from birth onward. In Ts65Dn corpus callosum, OLIG2+, CC1+, and NG2+ cells were equivalent at P7, but after P7 there were fewer OLIG2+ cells and a higher OPC-to-mature-oligodendrocyte ratio from P15; purified Ts65Dn OPCs showed no proliferation difference but reduced OLIG2+/MBP+ cells after 72 hr differentiation and more simple MBP+ morphology.

Methods

  • Postmortem human brain transcriptome: 58 paired tissue samples from 15 euploid control and 15 DS brains, ages 14 post-conception weeks to 42 years, across 11 regions including multiple neocortical areas, hippocampus, and cerebellar cortex. Affymetrix exon arrays were analyzed with paired t-tests for DEX genes (FDR < 0.1), WGCNA co-expression modules, and DAVID enrichment; findings were validated by ddPCR, immunoblotting, and spectral confocal reflectance microscopy.
  • Mouse validation: Ts65Dn and euploid B6EiC3 mice were used for immunoblotting, immunostaining, electron microscopy, electrophysiology, and immunopanning-based oligodendrocyte precursor cell cultures; developmental analyses spanned P7 to P60.
  • Cross-species comparison integrated human transcriptome modules with mouse oligodendrocyte lineage and myelin phenotypes.

Limitations

  • The paper does not include a dedicated limitations section. It states that individual-specific gene expression dysregulation domains (GEDDs) were not observable when comparing grouped samples, leaving unclear whether and how they underlie DS brain features; it also notes that Ts65Dn is trisomic for only ~100 orthologs of the 364 HSA21 genes.
  • Evident from the text: human transcriptome findings come from postmortem tissue with 15 DS and 15 control brains, and several mouse white matter findings are trends or non-significant (fewer myelinated axons p=0.1, n=6; thinner small-bore sheaths p=0.084 and p=0.076; fewer paranode cross-sections p=0.059). In Ts65Dn OPC cultures, reduced total OLIG2+ cells after differentiation suggested reduced viability, which may confound interpretation of maturation defects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neuron.2016.01.042

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

28 of 51 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Prior transcriptome studies of DS brains or derived pluripotent stem cells are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.

    “While several reports have investigated gene expression in postmortem human DS brains or derived pluripotent stem cells (Letourneau et al., 2014; Lockstone et al., 2007; Mao et al., 2003, 2005), these studies are limited by sparse genome coverage, numbers of samples or developmental time points, and potential variances between in vitro and in vivo gene regulation.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Letourneau et al., 2014 source
    • cites Lockstone et al., 2007 source

      The Abstract (page not provided) reports seven adult DS subjects and eight controls, and the Comparison with fetal DS brain section notes that the small fetal dataset reduced statistical power. The paper thus supports a sample-number limitation, but it used whole-genome microarrays, and its postmortem-brain study does not address differences between in vitro and in vivo gene regulation. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Mao et al., 2003, 2005

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

  • Premisecitation

    Deficits in myelination and oligodendrocyte maturation can lead to impaired formation of the nodes of Ranvier.

    “Deficits in myelination and oligodendrocyte maturation can also lead to impaired formation of the nodes of Ranvier (Kaplan et al., 2001; Rasband et al., 1999; Tanaka et al., 2009).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Kaplan et al., 2001 source

      The Results report that oligodendrocytes must mature before they effectively induce sodium-channel clustering, a step in developing nodes of Ranvier. The paper also suggests that myelination may be necessary for later Nav1.6 clustering, but does not establish that myelination deficits impair node formation as a whole. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Rasband et al., 1999 source

      The Shiverer mutant mice and Interactions with oligodendrocytes sections (page unavailable) report that mice lacking compact myelin and normal axoglial junctions had far fewer, often irregular nodal sodium-channel clusters. This supports impaired node formation with defective myelination, but the paper does not establish a deficit in oligodendrocyte maturation; it reports that oligodendrocytes were present. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Tanaka et al., 2009 source

      The Introduction (page unavailable) says myelination helps organize axons into nodal and paranodal segments, and the section on paranodal abnormalities reports abnormal junctions in the PLP1 transgenic mice. But the Introduction also says myelin was intact and ion-channel clusters formed normally at the nodes of Ranvier at the age studied. The paper therefore supports a link to paranodal abnormalities, not the claimed impairment of node formation from deficient myelination or oligodendrocyte maturation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingown data

    Intra-individual gene expression for astrocytes, neurons, and oligodendrocytes was highly correlated in all samples.

    “We found that intra-individual gene expression for these three cell types was highly correlated in all samples (see Table S8).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zhang et al., 2014 source

      In ‘Creation of an RNA-Seq transcriptome library’ (page unavailable), the paper reports high correlations among replicates of the same cell type, but lower correlations between different cell types. Its samples pooled cortices from multiple animals, so it does not establish intra-individual correlations for astrocytes, neurons, and oligodendrocytes in all samples. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Findingown data

    In CBC, the number of DEX genes remains constant throughout life.

    “A completely different temporal picture emerged in the CBC, where the number of DEX genes remains constant throughout life (Figure 1E, and Table S4).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Of 17,557 mRNA genes profiled, 842 (4.8%) in DFC and 571 (3.25%) in CBC were significantly differentially expressed between paired DS and euploid samples across all periods (FDR = 0.1).

    “Of 17,557 mRNA genes profiled, 842 (4.8%) and 571 (3.25%) genes in DFC and CBC, respectively, were defined as significantly differentially expressed (DEX) between paired DS and euploid samples across all periods (Table S3) (FDR = 0.1; see Extended Experimental Procedures).”
    Quote in the paperSubstantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    DFC and CBC were chosen for analyses because both regions have been implicated in DS neuropathology and exhibit diverse transcriptional profiles over development.

    “We chose dorsal frontal cortex (DFC) and CBC for our analyses because both regions have been implicated in DS neuropathology (Hartley et al., 2014; Haydar and Reeves, 2012; Letourneau et al., 2014; Lott, 2012) and exhibit diverse transcriptional profiles over the course of development (Kang et al., 2011; Tebbenkamp et al., 2014).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Hartley et al., 2014

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

    • cites Kang et al., 2011 source
    • cites Tebbenkamp et al., 2014 source

      The Introduction describes dynamic gene expression during human brain development and links expression patterns to regional specialization. The Autism spectrum disorders section discusses the frontal neocortex and cerebellum, but does not establish that both specifically exhibit diverse transcriptional profiles over development. The Down syndrome neuropathology rationale is attached to other citations, not Tebbenkamp et al. (LLM, conf=0.81)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes.

    “Together, these studies demonstrate that many genes throughout the genome are altered in DS, confirming and extending previous findings that non-HSA21 genes may contribute significantly to trisomy 21 phenotypes (Letourneau et al., 2014; Lockstone et al., 2007).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Letourneau et al., 2014 source
    • cites Lockstone et al., 2007 source

      The Discussion (page not available in our copy) reports numerous transcriptional changes throughout the genome in adult Down syndrome brain, supporting the claim that altered genes extend beyond chromosome 21. It does not establish that non-chromosome-21 genes contribute significantly to Down syndrome phenotypes; it cautions that the wider changes could instead be effects of defects and pathologies associated with Down syndrome. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Mouse models of DS have elucidated specific defects in neurogenesis, neuronal differentiation, and impaired synaptic plasticity and learning.

    “Mouse models have provided additional insights into the developmental progression of DS, elucidating specific defects in neurogenesis, neuronal differentiation, and impaired synaptic plasticity and learning (Chakrabarti et al., 2007, 2010; Hyde et al., 2001; Kleschevnikov et al., 2004; Siarey et al., 1997, 1999; Tyler and Haydar, 2013; Wang et al., 2013).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Chakrabarti et al., 2007, 2010

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

    • cites Hyde et al., 2001 source
    • cites Kleschevnikov et al., 2004 source

      The Results section ('Failed induction of LTP'; page unavailable) reports impaired hippocampal long-term potentiation in Ts65Dn mice, and the Discussion describes learning and memory deficits in these mice. The paper does not establish the cited sentence’s claims about defects in neurogenesis or neuronal differentiation, or their developmental progression. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Both intrinsic and extrinsic factors influence myelination.

    “Both intrinsic and extrinsic factors have been shown to influence myelination. For example, recent studies have shown that electrical activity drives myelination (Gibson et al., 2014; Ishibashi et al., 2006; Wake et al., 2011) and that synaptogenesis and myelination are linked.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Gibson et al., 2014 source
    • cites Ishibashi et al., 2006 source
    • cites Wake et al., 2011 source

      The paper reports that axonal electrical activity promotes myelin induction in mouse neuron–oligodendrocyte cultures, supporting the electrical-activity example for which it is cited. It also says the mechanism must be confirmed in vivo, so the unqualified statement that electrical activity drives myelination extends beyond what this study establishes. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Synaptogenesis and myelination are linked.

    “For example, recent studies have shown that electrical activity drives myelination (Gibson et al., 2014; Ishibashi et al., 2006; Wake et al., 2011) and that synaptogenesis and myelination are linked.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Gibson et al., 2014 source
    • cites Ishibashi et al., 2006 source
    • cites Wake et al., 2011 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The Ts65Dn mouse is trisomic for ~100 orthologs of the 364 genes on HSA21 and displays many DS-specific phenotypes, including delays in brain development and cognitive defects.

    “This commonly used DS model is trisomic for ~100 orthologs of the 364 genes on HSA21 and displays many DS-specific phenotypes, including delays in brain development and cognitive defects (Rueda et al., 2012).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Rueda et al., 2012 source

      Section 2 calls Ts65Dn a commonly used DS model and reports approximately 92 Hsa21-orthologous genes, reasonably close to the claim’s ~100. Sections 3 and 4 describe cognitive deficits and altered early brain development. However, Section 2 gives approximately 552 genes on the long arm of Hsa21, not 364, so the claimed HSA21 gene count is not supported. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Ongoing myelin remodeling throughout life may be important for learning, behavior, and cognition throughout adulthood.

    “Recent evidence in animal models indicates that ongoing myelin remodeling throughout life may be important for learning, behavior, and cognition throughout adulthood (Liu et al., 2012; McKenzie et al., 2014).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Liu et al., 2012 source

      The provided passages (labeled Abstract; no page numbers given) describe adult prefrontal-cortex myelin plasticity in mice and changes in social behavior after isolation and reintegration. They do not test learning or establish myelin remodeling throughout life, so the broader claim exceeds what this source supports. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites McKenzie et al., 2014 source

      The Abstract (page not provided) says that oligodendrocytes continue to form throughout life and that active myelination in adult mice is required for motor skill learning. The paper does not establish that myelin remodeling is important for behavior or cognition more broadly throughout adulthood; the ‘Running stimulates OP proliferation and OL production’ section says other types of learning remain to be tested. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Post-mortem studies show reduced myelin content and fewer oligodendrocytes in DS striatum.

    “This is in agreement both with previous studies showing that DS children manifest learning and memory problems in late infancy which often worsen in adolescence (Koo et al., 1992; Lanfranchi et al., 2010) and with post-mortem studies that show reduced myelin content (Abraham et al., 2012; Wisniewski, 1990; Wisniewski and Schmidt-Sidor, 1989) and fewer oligodendrocytes in DS striatum (Karlsen and P”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Abraham et al., 2012 source
    • cites Wisniewski, 1990

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

    • cites Karlsen and Pakkenberg, 2011 source

      The Basal Ganglia results report significantly fewer oligodendrocytes in post-mortem brains from older adults with Down syndrome than in controls. The counts are for the basal ganglia as a whole, which include the striatum; the paper does not report a separate striatal count. Reduced myelin content is attributed to other citations in the citing sentence, not to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Myelination is one of the most prolonged neurodevelopmental processes, continuing until the third decade of life.

    “Myelination is one of the most prolonged neurodevelopmental processes, continuing until the third decade of life (Benes et al., 1994; Fleschig, 1901; Miller et al., 2012; Yakovlev, 1967).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Benes et al., 1994 source
    • cites Fleschig, 1901

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

    • cites Miller et al., 2012 source

  • May combine two claims.

    Findingown data

    Myelinated axons in control brains form a grid-like lattice, but DS brains did not exhibit evidence of grid-like myelinated fiber orientations, suggesting reduced complexity of fiber pathways in the trisomic human brain.

    “In addition, we found that myelinated axons in control brains form a grid-like lattice that resembles a rectilinear grid as described previously (Ang et al., 2003; Wedeen et al., 2012) (Figure S6C). However, DS brains did not exhibit evidence of grid-like myelinated fiber orientations, suggesting reduced complexity of fiber pathways in the trisomic human brain.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Ang et al., 2003 source

      The Figure 2 caption (Laminar positioning; page unavailable) describes some Cajal–Retzius cell processes in developing mouse cortex as forming a rectilinear pattern, supporting the comparison to a grid. It does not describe myelinated axons or control human brains. The DS finding is presented as the citing authors’ own observation, not as a finding attributed to Ang et al. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Wedeen et al., 2012 source

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

    Premisecitation

    Electrical activity drives myelination.

    “For example, recent studies have shown that electrical activity drives myelination (Gibson et al., 2014; Ishibashi et al., 2006; Wake et al., 2011) and that synaptogenesis and myelination are linked.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites Gibson et al., 2014 source
    • cites Ishibashi et al., 2006 source
    • cites Wake et al., 2011 source

      The supplied paper text (labeled Abstract; page not provided) reports that electrical stimulation increased myelin induction in neuron–oligodendrocyte cultures, with increased myelination persisting after 16 days. It also says the mechanisms must be confirmed in vivo, so the unqualified claim that electrical activity drives myelination extends beyond the demonstrated culture setting. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Disturbances in myelin are associated with an increased rate of AD progression and byproducts of homeostatic myelin maintenance can promote the formation of amyloid plaques.

    “Consistent with this possibility, disturbances in myelin have been associated with an increased rate of AD progression and byproducts of homeostatic myelin maintenance can promote the formation of amyloid plaques (Bartzokis, 2007, 2011).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Bartzokis, 2007 source
    • cites Bartzokis, 2011 source

      Section 2.2 associates more severe myelin damage with the trajectory of decline into AD, but does not establish that myelin disturbances increase the rate of progression. Section 5 proposes that Aβ released during unsuccessful myelin repair could contribute to a mature neuritic plaque, supporting the claim's qualified plaque-formation mechanism. Page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The DFC is a brain region of late myelination which performs a critical role in the organization of behavioral, linguistic, and cognitive functions.

    “The present results clearly show a profound deficit in white matter maturation in individuals with DS during infancy and adolescence in DFC, a brain region of late myelination which performs a critical role in the organization of behavioral, linguistic, and cognitive functions (Fuster, 2002; Makinodan et al., 2012).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Fuster, 2002 source
    • cites Makinodan et al., 2012 source

      In the paper’s main text (page not provided), Makinodan et al. report a critical period of myelination in the mouse medial prefrontal cortex and link its maturation to social behavior and working memory. That supports a role in behavioral and cognitive function, but the paper does not establish that the DFC is a late-myelinating region or address linguistic functions. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Of the 121 mouse homologs of genes in M43, 67 met the cutoff for high expression (FPKM > 20), and 82.1% (55/67) of this subset were highly expressed by oligodendrocyte lineage cells.

    “We found that of the 121 mouse homologs of genes in M43, 67 met this cutoff for high expression (FPKM > 20) and 82.1% (55/67) of this subset were found to be highly expressed by oligodendrocyte lineage cells (gene names labeled in red in Figure 2B-D).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Zhang et al., 2014 source

      The RNA-Seq analysis and Additional information sections provide FPKM measurements for cortical cell types, including oligodendrocyte-lineage cells. But our copy does not identify M43 or report the 121 homologs, the 67 genes above FPKM 20, or the 55/67 proportion (searched for M43, those counts, and the cutoff). The citing sentence describes its authors’ own analysis rather than a result reported in the source paper. (LLM, conf=0.78)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Principal component analysis showed segregation between DS and control samples, but brain regions and age contributed more to global differences in gene expression than disease status.

    “Principal component analysis showed segregation between DS and control samples; however, brain regions and age (developmental periods) contributed more to the global differences in gene expression than disease status (Figure S2), indicating that gene expression in the human brain has a high degree of spatial variability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    All HSA21 DEX genes were up-regulated in DS samples, while only 47.7% (DFC) and 45.2% (CBC) of non-HSA21 DEX genes were up-regulated; 52.3% (DFC) and 54.8% (CBC) of non-HSA21 genes were down-regulated.

    “We also found that while all HSA21 DEX genes were up-regulated in DS samples, only 47.7% (DFC) and 45.2% (CBC) of non-HSA21 DEX genes were up-regulated. Conversely, 52.3% (DFC) and 54.8% (CBC) of non-HSA21 genes were down-regulated (Figure 1C), indicating that the triplication of HSA21 leads to both positive and negative regulation of genes on other chromosomes, (Figure S4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The dichotomy between DFC and CBC temporal gene expression profiles extended throughout the genome, with more variability across all chromosomes over developmental time in DFC samples.

    “This dichotomy between the DFC and CBC temporal gene expression profiles extended throughout the genome, with more variability across all chromosomes over developmental time in DFC samples (Figure S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    19.5% of HSA21 genes in DFC and 13.9% in CBC were DEX, while a median of 4.4% in DFC and 3.0% in CBC DEX genes were found on other chromosomes.

    “While 19.5% (DFC) and 13.9% (CBC) of the genes localized on HSA21 were DEX genes, a median of 4.4% (DFC) and 3.0% (CBC) DEX genes were found on other chromosomes in DS compared to their matched control.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Many of the altered genes in DS exhibit temporal and spatial specificity and are associated with distinct biological processes.

    “many of which exhibited temporal and spatial specificity and were associated with distinct biological processes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    These cellular and biochemical changes are first detected during the period of myelin development and refinement and are maintained at later ages (e.g., P60).

    “Importantly, these cellular and biochemical changes are first detected during the period of myelin development and refinement and are maintained at later ages (e.g., P60).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Quantification of nodal protein profiles in the Ts65Dn brain at P60 revealed a striking decrease in the number of nodes of Ranvier in the corpus callosum and similar decreases in the external capsule (p<0.005).

    “Quantification of nodal protein profiles in the Ts65Dn brain at P60 revealed a striking decrease in the number of nodes of Ranvier in the corpus callosum and we found similar decreases in the external capsule (Figure 5A-C; p<0.005).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Human mature oligodendrocyte genes were significantly enriched primarily in modules M8 and M43, and their trajectories indicate decreased expression in DS brains during development.

    “Conversely, human mature oligodendrocyte genes were found to be significantly enriched primarily in two modules, M8 and M43, and their trajectories indicate decreased expression in DS brains during development (Figure 7D,F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Module 43 (M43) was enriched for gene ontology categories related to regulation of action potential and axon ensheathment and was markedly down-regulated throughout the DS neocortex and in the HIP over development.

    “Notably, a module of co-expressed genes, number 43 (M43), was enriched for gene ontology categories related to regulation of action potential (BHA p=1.7×10-2) and axon ensheathment (BHA p=3.7×10-2) and was markedly down-regulated throughout the DS neocortex and in the HIP over development (Figure 2A, B and Table S6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    8 of the top 10 genes with highest intramodular connectivity (hub genes) in M43 were primarily expressed by mature oligodendrocytes and tightly correlated with other oligodendrocyte-associated M43 genes.

    “Importantly, 8 of the top 10 genes with highest intramodular connectivity (hub genes) in M43 were primarily expressed by mature oligodendrocytes and tightly correlated with other oligodendrocyte-associated M43 genes (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Action potential refractory periods were not different between groups, indicating that sodium channel kinetics are less likely to be responsible for the shift in the input-output relationship.

    “However, the action potential refractory periods were not different between groups, indicating that sodium channel kinetics are less likely to be responsible for the shift in the input-output relationship (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Many DEX genes display dynamic temporal and spatial differences in expression and highlight specific biological processes potentially disrupted in developing DS brain.

    “Most importantly, our results clearly show that many of these DEX genes display dynamic temporal and spatial differences in expression and highlight specific biological processes potentially disrupted in developing DS brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    These results indicate a decrease in the percentage of small-bore myelinated axons and myelin sheath thickness in Ts65Dn white matter.

    “Altogether, these results indicate a decrease in the percentage of small-bore myelinated axons and myelin sheath thickness in Ts65Dn white matter.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Differences in M43 accelerated over the course of DS neocortical development, coinciding with the onset and progression of myelination.

    “Differences in this module accelerated over the course of DS neocortical development (Figure 2A, B), coinciding with the onset and progression of myelination.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression of oligodendrocyte-specific genes was less correlated and significantly different between DS and control DFC (r = 0.89, p=0.018 Wilcoxon signed-rank test).

    “However, in agreement with our DEX analysis, expression of oligodendrocyte-specific genes were less correlated and significantly different between DS and control DFC (r = 0.89, p=0.018 Wilcoxon signed-rank test; Table S8).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Findingnone given

    The results implicate spatiotemporal disturbance in other molecular pathways in DS brain.

    “Our results also implicate spatiotemporal disturbance in other molecular pathways in DS brain, and provide a powerful data set for further computational and functional analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared to controls, there was a higher percentage of OLIG2+/NG2+ oligodendrocyte precursor cells and a decreased percentage of OLIG2+/CC1+ oligodendrocytes in Ts65Dn white matter from P15 on.

    “More importantly, compared to controls and as predicted by the human transcriptome study, there was a higher percentage of OLIG2+/NG2+ oligodendrocyte precursor cells and a decreased percentage of OLIG2+/CC1+ oligodendrocytes in Ts65Dn white matter from P15 on.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    NFASC and CNTNAP1 genes were significantly down-regulated from birth to adulthood in DS, and ddPCR analysis confirmed these differences.

    “These genes were significantly down-regulated from birth to adulthood (Figure 5F-G), and subsequent ddPCR analysis confirmed these differences in the DS brain samples (Figure 5H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During ensuing periods of active myelination and thereafter (after P7 and up to P60), there were fewer OLIG2+ cells in Ts65Dn white matter compared to controls, reaching significance at P60; this decline was not due to higher than normal apoptotic rates.

    “However, during the ensuing periods of active myelination and thereafter (after P7 and up to P60), there were fewer OLIG2+ cells in the Ts65Dn white matter compared to controls, reaching significance at P60; this decline in numbers was not due to higher than normal apoptotic rates (data not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lower levels of MAG gene expression spanning from birth to adulthood and lower levels of MBP gene expression from mid-fetal development to early childhood were observed in DS.

    “Lower levels of gene expression spanning from birth to adulthood for myelin associated glycoprotein (MAG; Figure 3A) and from mid-fetal development to early childhood for myelin basic protein (MBP; Figure 3B) were observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Gene expression levels for markers of astrocytes, neurons, and oligodendrocytes were highly correlated for the same brain regions in all control (r > 0.94) or DS individuals (r > 0.95), indicating uniform tissue collection procedures.

    “We further found by pair-wise analysis that gene expression levels for markers of all three cell types were highly correlated for the same brain regions in all control (r > 0.94) or DS individuals (r > 0.95), indicating uniform tissue collection procedures.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Previous studies show that DS children manifest learning and memory problems in late infancy which often worsen in adolescence.

    “This is in agreement both with previous studies showing that DS children manifest learning and memory problems in late infancy which often worsen in adolescence (Koo et al., 1992; Lanfranchi et al., 2010) and with post-mortem studies that show reduced myelin content (Abraham et al., 2012; Wisniewski, 1990; Wisniewski and Schmidt-Sidor, 1989) and fewer oligodendrocytes in DS striatum (Karlsen and P”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Koo et al., 1992 source
    • cites Lanfranchi et al., 2010 source

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

    Premisecitation

    Nearly all adults with DS develop dementia starting in the third decade of life.

    “Nearly all adults with DS develop dementia starting in the third decade of life (Sheehan et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sheehan et al., 2014 source

  • May combine two claims.

    Interpretationown data

    Dysregulation of genes on HSA21 is likely the first genome-level disturbance, and gene expression changes on other chromosomes follow quickly thereafter (cascade hypothesis).

    “Our transcriptome analyses support a “cascade hypothesis” in which dysregulation of genes on HSA21 is likely the first genome-level disturbance and that gene expression changes on other chromosomes follow quickly thereafter.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The DS altered gene expression follows a consistent pattern, with increased and decreased gene-expression levels alternating across large chromosomal segments (GEDDs).

    “It has been recently shown by Letourneau et al. (2014) in fibroblasts from monozygotic twins discordant for trisomy 21, that the DS altered gene expression follows a consistent pattern, with increased and decreased gene-expression levels alternating across large chromosomal segments, which they named gene expression dysregulation domains (GEDDs).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Letourneau et al. (2014) source

  • May combine two claims.

    Interpretationown data

    The relevant WGCNA modules exhibit similar trajectories when compared with expression changes of individual oligodendrocyte-lineage genes, demonstrating that these cell type-specific defects in oligodendroglial development are associated with complex gene network disturbances in the DS brain.

    “Thus, the relevant WGCNA modules exhibit similar trajectories when compared with the expression changes of individual oligodendrocyte-lineage genes, demonstrating that these cell type-specific defects in oligodendroglial development are associated with complex gene network disturbances in the DS brain.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Strategies to enhance myelination may serve as therapeutic targets to attenuate the cognitive and neurological symptoms of DS.

    “In summary, our findings indicate that strategies to enhance myelination may therefore serve as therapeutic targets to attenuate the cognitive and neurological symptoms of DS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    These systems level changes impact cellular development and play a functional role in brain maturation.

    “Most importantly, by elucidating the in vivo impact of the white matter-associated gene modules as an example, we show that these systems level changes impact cellular development and play a functional role in brain maturation.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    The biological processes affected by trisomy 21 and the HSA21 and non-HSA21 genes associated with those processes are not fully understood.

    “While it is clear that trisomy of HSA21 is the root cause of DS, which biological processes are affected and which HSA21 and non-HSA21 genes are associated with those processes are not fully understood.”

  • The paper relies on this without support.

    The extent to which human postmortem neuropathology is reflected in mouse models (and vice versa) remains one of the key problems hampering further understanding of DS brain development and function.

    “Furthermore, the extent to which human postmortem neuropathology is reflected in the mouse models (and vice versa) remains one of the key problems hampering further understanding of DS brain development and function.”

  • The paper relies on this without support.

    Changes in white matter have not been previously described in the Ts65Dn mouse brain.

    “However, changes in white matter have not been previously described in the Ts65Dn mouse brain.”

  • The paper relies on this without support.

    In vitro differentiation of Ts65Dn oligodendrocytes reflects cell-autonomous effects in vivo.

    “Taken together, these cell culture experiments indicate that Ts65Dn oligodendrocytes exhibit cell-autonomous impairments in oligodendrocyte maturation and viability, but not proliferation.”

  • The paper relies on this without support.

    Postmortem human brain transcriptomes reflect in vivo developmental gene expression.

    “This study was conducted using de-identified postmortem human brain specimens from tissue collections at the Department of Neuroscience, Yale School of Medicine, the University of Maryland Brain and Tissue Bank (Baltimore, MD), Brigham and Women's Hospital Pathology Department, and Boston University Pathology Department.”
5 of 5

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?

  • Only one comprehensive analysis of human developmental tissue that identifies the molecular and cellular pathways disrupted during brain development in Down syndrome exists.

    “Currently, only one comprehensive analysis of human developmental tissue that identifies the molecular and cellular pathways that are disrupted during brain development in DS exists39.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [39]

    The Discussion describes this as the most comprehensive developmental gene-expression analysis of human Down syndrome brains to date, and the Introduction says earlier studies had important limitations. These passages support identifying the paper as a comprehensive analysis of disrupted developmental processes, but they do not establish the citing sentence’s stronger claim that it is the only one currently in existence. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Evidence of altered regulation of neuronal differentiation genes during the period of neurogenesis is consistent with increased neuronal differentiation, which would suggest premature cell cycle exit.

    “Evidence of altered regulation of neuronal differentiation genes during the period of neurogenesis is consistent with increased neuronal differentiation, which would suggest premature cell cycle exit39.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [39]

    The Results section on co-dysregulation reports altered gene-expression modules associated with neuronal differentiation (M4 and M45). It does not establish that these changes occurred specifically during neurogenesis, indicate increased neuronal differentiation, or suggest premature cell-cycle exit. No page number is available in our copy. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • This transcriptomic investigation of the cortex and cerebellum of individuals with Down syndrome from prenatal stages to adulthood found genome-wide alterations in the expression of a large number of genes, many with temporal and spatial specificity and associated with distinct biological processes, including metabolism.

    “This transcriptomic (microarray) investigation of the cortex and cerebellum of individuals with DS from prenatal stages to adulthood has found genome-wide alterations in the expression of a large number of genes (see Box 3), many of which exhibited temporal and spatial specificity and were associated with distinct biological processes, including metabolism (Box 4).”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [39]

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

    Experimental — accuracy not yet measured

  • Altered development of the cortex in Down syndrome includes both reduced neurogenesis early in development and altered gliogenesis and myelination later in development.

    “Altered development of the cortex in DS includes both reduced neurogenesis early in development and altered gliogenesis and myelination later in development39 (Fig. 2).”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [39]

    The Results (no page given) report altered oligodendrocyte differentiation and reduced myelination in the developing Down syndrome neocortex, supporting the later-development part of the claim. The Introduction (no page given) mentions neurogenesis defects in mouse models, but does not establish reduced early neurogenesis in the human cortex; the findings also concern oligodendrocytes rather than gliogenesis broadly. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Studies using transcriptomics and new analytical tools have suggested that neurogenesis, gliogenesis and myelination may be temporally altered in Down syndrome.

    “Indeed, studies using transcriptomics and new analytical tools have suggested that neurogenesis, gliogenesis and myelination may be temporally altered in DS39,106,107.”

    From Consequences of trisomy 21 for brain development in Down syndrome (2024) · cites this paper as [39]

    The Results (page unavailable) report developmental changes in genes associated with oligodendrocyte differentiation and myelination in Down syndrome, and identify altered neuronal-differentiation gene modules. The Introduction (page unavailable) reports neurogenesis defects from earlier mouse studies. This paper does not establish temporal alteration of neurogenesis and gliogenesis as broadly as the citing sentence suggests. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Related

Authors
Olmos-Serrano, J. L., Kang, H. J., Tyler, W. A., Silbereis, J. C., Cheng, F., Zhu, Y., Pletikos, M., Jankovic-Rapan, L., Cramer, N. P., Galdzicki, Z., Goodliffe, J., Peters, A., Sethares, C., Delalle, I., Golden, J. A., Haydar, T. F., & Sestan, N.
Affiliations
  • Boston University (US)
  • Yale University (US)
  • University of South Florida (US)
  • Uniformed Services University of the Health Sciences (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Haydar, Tarik F.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2016-03
Volume
89
Issue
6
Pages
1208-1222
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2016.01.042
PMC
PMC4795969
OpenAlex
W2287180374
Cited by
239
References
70
Citations by year
2026: 16 · 2025: 22 · 2024: 21 · 2023: 26 · 2022: 28 · 2021: 34 · 2020: 26 · 2019: 23 · 2018: 16 · 2017: 15 · 2016: 12
FWCI
19.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
  • NIH (NS076503, MH103339, MH105972, MH106934)
  • intramural USUHS grants
  • Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C2461)
  • Kavli Foundation
  • James S. McDonnell Foundation scholar award
  • Ruth Kirschstein National Research Service Award (NRSA) fellowship
  • China Scholarship Council fellowship
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
Down syndrome, oligodendrocyte differentiation, myelination, hypomyelination, white matter development, Ts65Dn mouse model, brain transcriptome, developmental delay, intellectual disability, action potential propagation, neocortex, neuropathogenesis
MeSH terms
Action Potentials, Adolescent, Adult, Animals, Brain, Cell Differentiation, Child, Child, Preschool, Chromosomes, Human, Pair 17, Disease Models, Animal, Down Syndrome, Myelin Basic Protein, Female, Humans, Infant, Infant, Newborn, Male, Mice, Transgenic, Mosaicism, Myelin Sheath, Neural Conduction, Oligodendroglia, Postmortem Changes, Trisomy, Gene Expression Regulation, Developmental, Gene Expression Profiling, Mice, Young Adult, White Matter

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 by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-27.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-27.

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.

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