CoChat
Sign Up
Cited by 118Axon Guidance and Neuronal SignalingDevelopmental Biology and Gene RegulationNeurogenesis and neuroplasticity mechanisms

RGMs: Structural Insights, Molecular Regulation, and Downstream Signaling

Open access
Siebold, Christian, Yamashita, Toshihide, Monnier, Philippe P., Mueller, Bernhard K., Pasterkamp, R. Jeroen·2017·Trends in Cell Biology
DOI 10.1016/j.tcb.2016.11.009PMC PMC5404723
Open this paper in CoChat — free account

Abstract

Although originally discovered as neuronal growth cone-collapsing factors, repulsive guidance molecules (RGMs) are now known as key players in many fundamental processes, such as cell migration, differentiation, iron homeostasis, and apoptosis, during the development and homeostasis of many tissues and organs, including the nervous, skeletal, and immune systems. Furthermore, three RGMs (RGMa, RGMb/DRAGON, and RGMc/hemojuvelin) have been linked to the pathogenesis of various disorders ranging from multiple sclerosis (MS) to cancer and juvenile hemochromatosis (JHH). While the molecular details of these (patho)biological effects and signaling modes have long remained unknown, recent studies unveil several exciting and novel aspects of RGM processing, ligand-receptor interactions, and downstream signaling. In this review, we highlight recent advances in the mechanisms-of-action and function of RGM proteins.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.tcb.2016.11.009

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 68

  1. [1]Kolodkin AL Pasterkamp RJ SnapShot: axon guidance II Cell 2013 153 722.e1 23622251
  2. [2]Severyn CJ Molecular biology, genetics and biochemistry of the repulsive guidance molecule family Biochem J 2009 422 393 403 19698085 PMC4242795
  3. [3]Rajagopalan S Neogenin mediates the action of repulsive guidance molecule Nat Cell Biol 2004 6 756 762 15258590
  4. [4]Matsunaga E RGM and its receptor neogenin regulate neuronal survival Nat Cell Biol 2004 6 749 755 15258591
  5. [6]Babitt JL Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor J Biol Chem 2005 280 29820 29827 15975920
  6. [7]Samad TA DRAGON, a bone morphogenetic protein co-receptor J Biol Chem 2005 280 14122 14129 15671031
  7. [8]Corradini E The RGM/DRAGON family of BMP co-receptors Cytokine Growth Factor Rev 20 389 398 PMC3715994 19897400
  8. [9]Zhou Z Neogenin regulation of BMP-induced canonical Smad signaling and endochondral bone formation Dev Cell 2010 19 90 102 20643353 PMC2924163
  9. [10]Tian C Liu J Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling Mol Reprod Dev 2013 80 700 717 23740870 PMC4440832
  10. [11]Demicheva E Targeting repulsive guidance molecule A to promote regeneration and neuroprotection in multiple sclerosis Cell Rep 2015 10 1887 1898 25801027
  11. [12]Feng J RNA interference against repulsive guidance molecule A improves axon sprout and neural function recovery of rats after MCAO/reperfusion Exp Neurol 2012 238 235 242 22921459
  12. [13]Hata K RGMa inhibition promotes axonal growth and recovery after spinal cord injury J Cell Biol 2006 173 47 58 16585268 PMC2063787
  13. [14]Tanabe S Yamashita T Repulsive guidance molecule-a is involved in Th17-cell-induced neurodegeneration in autoimmune encephalomyelitis Cell Rep 2014 9 1459 1470 25456136
  14. [15]Shabanzadeh AP Uncoupling Neogenin association with lipid rafts promotes neuronal survival and functional recovery after stroke Cell Death Dis 2015 6 e1744 25950474 PMC4669689
  15. [16]Bell CH Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub Science 2013 341 77 80 23744777 PMC4730555
  16. [17]Healey EG Repulsive guidance molecule is a structural bridge between neogenin and bone morphogenetic protein Nat Struct Mol Biol 2015 22 458 465 25938661 PMC4456160
  17. [18]Yang F Neogenin interacts with hemojuvelin through its two membrane-proximal fibronectin type III domains Biochemistry 2008 47 4237 4245 18335997 PMC2819367
  18. [19]Wu Q Repulsive guidance molecule (RGM) family proteins exhibit differential binding kinetics for bone morphogenetic proteins (BMPs) PLoS One 2012 7 e46307 23029472 PMC3459908
  19. [20]Hartung A Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling Mol Cell Biol 2006 26 7791 7805 16923969 PMC1636853
  20. [21]Di Guglielmo GM Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover Nat Cell Biol 2003 5 410 421 12717440
  21. [22]Vieira AV Control of EGF receptor signaling by clathrin-mediated endocytosis Science 1996 274 2086 2089 8953040
  22. [23]Le Roy C Wrana JL Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling Nat Rev Mol Cell Biol 2005 6 112 126 15687999
  23. [24]Zhang A-S Interaction of hemojuvelin with neogenin results in iron accumulation in human embryonic kidney 293 cells J Biol Chem 2005 280 33885 33894 16103117
  24. [25]Zhang A-S Hemojuvelin-neogenin interaction is required for bone morphogenic protein-4-induced hepcidin expression J Biol Chem 2009 284 22580 22589 19564337 PMC2755665
  25. [26]Tian C The neogenin/DCC homolog UNC-40 promotes BMP signaling via the RGM protein DRAG-1 in C. elegans Development 2013 140 4070 4080 24004951 PMC3775419
  26. [27]Tassew NG Modifying lipid rafts promotes regeneration and functional recovery Cell Rep 2014 8 1146 1159 25127134
  27. [28]Lee D-H Neogenin inhibits HJV secretion and regulates BMP-induced hepcidin expression and iron homeostasis Blood 2010 115 3136 3145 20065295 PMC2858467
  28. [29]Monnier PP RGM is a repulsive guidance molecule for retinal axons Nature 2002 419 392 395 12353034
  29. [30]Wilson NH Key B Neogenin interacts with RGMa and netrin-1 to guide axons within the embryonic vertebrate forebrain Dev Biol 2006 296 485 498 16836993
  30. [31]Kee N Neogenin and RGMa control neural tube closure and neuroepithelial morphology by regulating cell polarity J Neurosci 2008 28 12643 12653 19036958 PMC6671791
  31. [32]Muramatsu R RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis Nat Med 2011 17 488 494 21423182
  32. [33]Mirakaj V Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation Proc Natl Acad Sci USA 2011 108 6555 6560 21467223 PMC3080996
  33. [34]Yamashita T Neogenin and repulsive guidance molecule signaling in the central nervous system Curr Opin Neurobiol 2007 17 29 34 17169551
  34. [35]De Vries M Cooper HM Emerging roles for neogenin and its ligands in CNS development J Neurochem 2008 106 1483 1492 18485097
  35. [36]Lanzara C Spectrum of hemojuvelin gene mutations in 1q–linked juvenile hemochromatosis Blood 2004 103 4317 4321 14982873
  36. [37]Lee PL Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis Br J Haematol 2004 127 224 339 15461631
  37. [38]Tassew NG SKI-1 and Furin generate multiple RGMa fragments that regulate axonal growth Dev Cell 2012 22 391 402 22340500
  38. [39]Silvestri L Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis Blood 2007 109 4503 4510 17264300
  39. [41]Maxson JE Matriptase-2- and proprotein convertase-cleaved forms of hemojuvelin have different roles in the down-regulation of hepcidin expression J Biol Chem 2010 285 39021 39028 20937842 PMC2998150
  40. [42]Guillem F Inactive matriptase-2 mutants found in IRIDA patients still repress hepcidin in a transfection assay despite having lost their serine protease activity Hum Mutat 2012 33 1388 1396 22581667
  41. [43]Brinks H The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus J Neurosci 2004 24 3862 3869 15084667 PMC6729353
  42. [44]Matsunaga E Repulsive guidance molecule plays multiple roles in neuronal differentiation and axon guidance J Neurosci 2006 26 6082 6088 16738252 PMC6675224
  43. [45]Conrad S Neogenin-RGMa signaling at the growth cone is bone morphogenetic protein-independent and involves RhoA, ROCK, and PKC J Biol Chem 2007 282 16423 16433 17389603
  44. [46]Tassew NG Sustained in vivo inhibition of protein domains using single-chain Fv recombinant antibodies and its application to dissect RGMa activity on axonal outgrowth J Neurosci 2009 29 1126 1131 19176821 PMC6665128
  45. [47]Niederkofler V Repulsive guidance molecule (RGM) gene function is required for neural tube closure but not retinal topography in the mouse visual system J Neurosci 2004 24 808 818 14749425 PMC6729817
  46. [48]van Erp S Lrig2 negatively regulates ectodomain shedding of axon guidance receptors by ADAM proteases Dev Cell 2015 35 537 552 26651291
  47. [49]Kam JWK RGMB and neogenin control cell differentiation in the developing olfactory epithelium Development 2016 143 1534 1546 27143755
  48. [50]Hata K Unc5B associates with LARG to mediate the action of repulsive guidance molecule J Cell Biol 2009 184 737 750 19273616 PMC2686409
  49. [51]Endo M Yamashita T Inactivation of Ras by p120GAP via focal adhesion kinase dephosphorylation mediates RGMa-induced growth cone collapse J Neurosci 2009 29 6649 6662 19458235 PMC6665895
  50. [52]Okamura Y TACE cleaves neogenin to desensitize cortical neurons to the repulsive guidance molecule Neurosci Res 2011 71 63 70 21645559
  51. [53]Banerjee P γ-secretase and LARG mediate distinct RGMa activities to control appropriate layer targeting within the optic tectum Cell Death Differ 2016 23 442 453 26292756 PMC5072438
  52. [54]Goldschneider D The neogenin intracellular domain regulates gene transcription via nuclear translocation Mol Cell Biol 2008 28 4068 4079 18391016 PMC2423113
  53. [55]Schaffar G LIM-only protein 4 interacts directly with the repulsive guidance molecule A receptor Neogenin J Neurochem 2008 107 418 431 18702663
  54. [56]Neuhaus-Follini A Bashaw GJ The intracellular domain of the Frazzled/DCC receptor is a transcription factor required for commissural axon guidance Neuron 2015 87 751 763 26291159 PMC4754793
  55. [57]Asprer JST LMO4 functions as a co-activator of neurogenin 2 in the developing cortex Development 2011 138 2823 2832 21652654 PMC3109604
  56. [58]Mueller TD RGM co-receptors add complexity to BMP signaling Nat Struct Mol Biol 2015 22 439 440 26036568
  57. [59]Ma CHE The BMP coreceptor RGMb promotes while the endogenous BMP antagonist noggin reduces neurite outgrowth and peripheral nerve regeneration by modulating BMP signaling J Neurosci 2011 31 18391 18400 22171041 PMC3243947
  58. [60]Mawdsley DJ The Netrin receptor Neogenin is required for neural tube formation and somitogenesis in zebrafish Dev Biol 2004 269 302 315 15081375
  59. [61]Kee N Netrin-1 is required for efficient neural tube closure Dev Neurobiol 2013 73 176 187 22888057
  60. [62]Lee NK Neogenin recruitment of the WAVE regulatory complex maintains adherens junction stability and tension Nat Commun 2016 7 11082 27029596 PMC4821876
  61. [63]Stahl B Biochemical characterization of a putative axonal guidance molecule of the chick visual system Neuron 1990 5 735 743 2171592
  62. [64]Müller BK Chromophore-assisted laser inactivation of a repulsive axonal guidance molecule Curr Biol 1996 6 1497 1502 8939610
  63. [65]Xia Y Dragon (Repulsive Guidance Molecule b) Inhibits IL-6 Expression in macrophages J Immunol 2011 186 1369 1376 21187450 PMC3670585
  64. [66]Li J Repulsive guidance molecule B inhibits metastasis and is associated with decreased mortality in non-small cell lung cancer Oncotarget 2016 7 15678 15689 26910889 PMC4941269
  65. [67]Hesson LB Integrated genetic, epigenetic, and transcriptional profiling identifies molecular pathways in the development of laterally spreading tumors Mol Cancer Res 2016 10.1158/1541-7786.MCR-16-0175 27671336 · DOI
  66. [68]Li VSW Frequent inactivation of axon guidance molecule RGMA in human colon cancer through genetic and epigenetic mechanismS Gastroenterology 2009 137 176 187 19303019
  67. [70]Huang FW A mouse model of juvenile hemochromatosis J Clin Invest 2005 115 2187 2191 16075059 PMC1180543
  68. [71]Tawfik A Deletion of hemojuvelin, an iron-regulatory protein, in mice results in abnormal angiogenesis and vasculogenesis in retina along with reactive gliosis Investig Opthalmology Vis Sci 2014 55 3616 PMC4053073 24812553

Cited by

Sorted by citations

Authors
Siebold, C., Yamashita, T., Monnier, P. P., Mueller, B. K., & Pasterkamp, R. J.
Affiliations
  • Centre for Human Genetics (GB)
  • The University of Osaka (JP)
  • Krembil Research Institute (CA)
  • AbbVie (Germany) (DE)
  • University Medical Center Utrecht (NL)
Corresponding author
Pasterkamp, R. Jeroen
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2017-05
Volume
27
Issue
5
Pages
365-378
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2016.11.009
PMC
PMC5404723
OpenAlex
W2563225587
Cited by
118
References
3
Citations by year
2026: 5 · 2025: 19 · 2024: 17 · 2023: 10 · 2022: 14 · 2021: 23 · 2020: 11 · 2019: 10 · 2018: 6 · 2017: 3
FWCI
0.70
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Oxford University Research Archive (ORA) (University of Oxford) (acceptedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Utrecht University Repository (Utrecht University) (submittedVersion)
Funders
  • Cancer Research UK (14414)
  • Medical Research Council (MR/L017776/1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
repulsive guidance molecules, RGMa, ligand-receptor interactions, downstream signaling, cell migration, iron homeostasis, apoptosis, cell differentiation, multiple sclerosis, cancer, juvenile hemochromatosis, brain development, skeletal development, immune system development
MeSH terms
Animals, Multigene Family, Humans, Ligands, Models, Biological, Nerve Tissue Proteins, Receptors, Cell Surface, Signal Transduction

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.

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