Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

CNS integrins switch growth factor signalling to promote target-dependent survival

Nature Cell Biology volume 4, pages 833–841 (2002)Cite this article

Abstract

Depending on the stage of development, a growth factor can mediate cell proliferation, survival or differentiation. The interaction of cell-surface integrins with extracellular matrix ligands can regulate growth factor responses and thus may influence the effect mediated by the growth factor. Here we show, by using mice lacking the α6 integrin receptor for laminins, that myelin-forming oligodendrocytes activate an integrin-regulated switch in survival signalling when they contact axonal laminins. This switch alters survival signalling mediated by neuregulin from dependence on the phosphatidylinositol-3-OH kinase (PI(3)K) pathway to dependence on the mitogen-activated kinase pathway. The consequent enhanced survival provides a mechanism for target-dependent selection during development of the central nervous system. This integrin-regulated switch reverses the capacity of neuregulin to inhibit the differentiation of precursors, thereby explaining how neuregulin subsequently promotes differentiation and survival in myelinating oligodendrocytes. Our results provide a general mechanism by which growth factors can exert apparently contradictory effects at different stages of development in individual cell lineages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Loss of MBP-positive oligodendrocytes in the brainstem of α6-null mice.
Figure 2: Laminin is found on myelinating axon tracts.
Figure 3: α6-null neural precursors develop fewer myelinating oligodendrocytes.
Figure 4: NRG-mediated survival is enhanced on laminin-2 and is independent of PI(3)K.
Figure 5: MAPK signalling is required for NRG/α6β1 survival.
Figure 6: BAD phosphorylation on Ser 112 is regulated by α6β1.
Figure 7: NRG inhibition of differentiation is blocked by laminin.
Figure 8: Model of integrin–growth-factor synergy.

Similar content being viewed by others

References

  1. Barres, B. A. & Raff, M. C. Control of oligodendrocyte number in the developing rat optic nerve. Neuron 12, 935–942 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Barres, B. A. & Raff, M. C. Axonal control of oligodendrocyte development. J. Cell Biol. 147, 1123–1128 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Buonanno, A. & Fischbach, G. D. Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr. Opin. Neurobiol. 11, 287–296 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Barres, B. A. et al. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70, 31–46 (1992).

    Article  CAS  PubMed  Google Scholar 

  5. Noble, M., Murray, K., Stroobant, P., Waterfield, M. D. & Riddle, P. Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. Nature 333, 560–562 (1988).

    Article  CAS  PubMed  Google Scholar 

  6. Canoll, P. D. et al. GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 17, 229–243 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Canoll, P. D., Kraemer, R., Teng, K. K., Marchionni, M. A. & Salzer, J. L. GGF/neuregulin induces a phenotypic reversion of oligodendrocytes. Mol. Cell. Neurosci. 13, 79–94 (1999).

    Article  CAS  PubMed  Google Scholar 

  8. Calaora, V. et al. Neuregulin signaling regulates neural precursor growth and the generation of oligodendrocytes in vitro. J. Neurosci. 21, 4740–4751 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ebner, S., Dunbar, M. & McKinnon, R. D. Distinct roles for PI3K in proliferation and survival of oligodendrocyte progenitor cells. J. Neurosci. Res. 62, 336–345 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Calver, A. R. et al. Oligodendrocyte population dynamics and the role of PDGF in vivo. Neuron 20, 869–882 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Flores, A. I. et al. Akt-mediated survival of oligodendrocytes induced by neuregulins. J. Neurosci. 20, 7622–7630 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fernandez, P. A. et al. Evidence that axon-derived neuregulin promotes oligodendrocyte survival in the developing rat optic nerve. Neuron 28, 81–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  13. Giancotti, F. G. & Ruoslahti, E. Integrin signaling. Science 285, 1028–1032 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Milner, R. & ffrench-Constant, C. A developmental analysis of oligodendroglial integrins in primary cells: changes in αv-associated β subunits during differentiation. Development 120, 3497–3506 (1994).

    CAS  PubMed  Google Scholar 

  15. Milner, R. et al. Expression of αvβ3 and αvβ8 integrins during oligodendrocyte precursor differentiation in the presence and absence of axons. Glia 21, 350–360 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Blaschuk, K. L., Frost, E. E. & ffrench-Constant, C. The regulation of proliferation and differentiation in oligodendrocyte progenitor cells by αV integrins. Development 127, 1961–1969 (2000).

    CAS  PubMed  Google Scholar 

  17. Milner, R., Edwards, G., Streuli, C. & ffrench-Constant, C. A role in migration for the αvβ1 integrin expressed on oligodendrocyte precursors. J. Neurosci. 16, 7240–7252 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Frost, E. E., Buttery, P. C., Milner, R. & ffrench-Constant, C. Integrins mediate a neuronal survival signal for oligodendrocytes. Curr. Biol. 9, 1251–1254 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Morissette, N. & Carbonetto, S. Laminin α2 chain (M chain) is found within the pathway of avian and murine retinal projections. J. Neurosci. 15, 8067–8082 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tian, M. et al. Laminin-α2 chain-like antigens in CNS dendritic spines. Brain Res. 764, 28–38 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Powell, S. K., Williams, C. C., Nomizu, M., Yamada, Y. & Kleinman, H. K. Laminin-like proteins are differentially regulated during cerebellar development and stimulate granule cell neurite outgrowth in vitro. J. Neurosci. Res. 54, 233–247 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. McGowan, K. A. & Marinkovich, M. P. Laminins and human disease. Microsc. Res. Tech. 51, 262–279 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Georges-Labouesse, E. et al. Absence of integrin α6 leads to epidermolysis bullosa and neonatal death in mice. Nature Genet. 13, 370–373 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Reynolds, B. A. & Weiss, S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255, 1707–1710 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Vartanian, T., Goodearl, A., Viehover, A. & Fischbach, G. Axonal neuregulin signals cells of the oligodendrocyte lineage through activation of HER4 and Schwann cells through HER2 and HER3. J. Cell Biol. 137, 211–220 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Osterhout, D. J., Wolven, A., Wolf, R. M., Resh, M. D. & Chao, M. V. Morphological differentiation of oligodendrocytes requires activation of Fyn tyrosine kinase. J. Cell Biol. 145, 1209–1218 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kramer, E. M., Klein, C., Koch, T., Boytinck, M. & Trotter, J. Compartmentation of Fyn kinase with glycosylphosphatidylinositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination. J. Biol. Chem. 274, 29042–29049 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Sperber, B. R. et al. A unique role for Fyn in CNS myelination. J. Neurosci. 21, 2039–2047 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shimamura, A., Ballif, B. A., Richards, S. A. & Blenis, J. Rsk1 mediates a MEK–MAP kinase cell survival signal. Curr. Biol. 10, 127–135 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Park, S. K., Miller, R., Krane, I. & Vartanian, T. The erbB2 gene is required for the development of terminally differentiated spinal cord oligodendrocytes. J. Cell Biol. 154, 1245–1258 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Georges-Labouesse, E., Mark, M., Messaddeq, N. & Gansmuller, A. Essential role of α6 integrins in cortical and retinal lamination. Curr. Biol. 8, 983–986 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Lallier, T. E., Whittaker, C. A. & DeSimone, D. W. Integrin α6 expression is required for early nervous system development in Xenopus laevis. Development 122, 2539–2554 (1996).

    CAS  PubMed  Google Scholar 

  33. Zhang, Z. & Galileo, D. S. Retroviral transfer of antisense integrin α6 or α8 sequences results in laminar redistribution or clonal cell death in developing brain. J. Neurosci. 18, 6928–6938 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Burne, J. F., Staple, J. K. & Raff, M. C. Glial cells are increased proportionally in transgenic optic nerves with increased numbers of axons. J. Neurosci. 16, 2064–2073 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. David, S., Miller, R. H., Patel, R. & Raff, M. C. Effects of neonatal transection on glial cell development in the rat optic nerve: evidence that the oligodendrocyte-type 2 astrocyte cell lineage depends on axons for its survival. J. Neurocytol. 13, 961–974 (1984).

    Article  CAS  PubMed  Google Scholar 

  36. Pinkas-Kramarski, R. et al. Brain neurons and glial cells express Neu differentiation factor/heregulin: a survival factor for astrocytes. Proc. Natl Acad. Sci. USA 91, 9387–9391 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Corley, S. M., Ladiwala, U., Besson, A. & Yong, V. W. Astrocytes attenuate oligodendrocyte death in vitro through an α6 integrin–laminin-dependent mechanism. Glia 36, 281–294 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Meyer, D. & Birchmeier, C. Multiple essential functions of neuregulin in development. Nature 378, 386–390 (1995).

    Article  CAS  PubMed  Google Scholar 

  39. Frisch, S. M. & Screaton, R. A. Anoikis mechanisms. Curr. Opin. Cell Biol. 13, 555–562 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Osterhout, D. J., Marin-Husstege, M., Abano, P. & Casaccia-Bonnefil, P. Molecular mechanisms of enhanced susceptibility to apoptosis in differentiating oligodendrocytes. J. Neurosci. Res. 69, 24–29 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Baron, W., Metz, B., Bansal, R., Hoekstra, D. & de Vries, H. PDGF and FGF-2 signaling in oligodendrocyte progenitor cells: regulation of proliferation and differentiation by multiple intracellular signaling pathways. Mol. Cell. Neurosci. 15, 314–329 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Stariha, R. L. et al. Role of extracellular signal-regulated protein kinases 1 and 2 in oligodendroglial process extension. J. Neurochem. 68, 945–953 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Richardson, W. D., Pringle, N., Mosley, M. J., Westermark, B. & Dubois-Dalcq, M. A role for platelet-derived growth factor in normal gliogenesis in the central nervous system. Cell 53, 309–319 (1988).

    Article  CAS  PubMed  Google Scholar 

  44. Vemuri, G. S. & McMorris, F. A. Oligodendrocytes and their precursors require phosphatidylinositol 3-kinase signaling for survival. Development 122, 2529–2537 (1996).

    CAS  PubMed  Google Scholar 

  45. Almeida, E. A. et al. Mouse egg integrin α6β1 functions as a sperm receptor. Cell 81, 1095–1104 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Vitry, S., Avellana-Adalid, V., Hardy, R., Lachapelle, F. & Baron-Van Evercooren, A. Mouse oligospheres: from pre-progenitors to functional oligodendrocytes. J. Neurosci. Res. 58, 735–751 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Ranscht, B., Clapshaw, P. A., Price, J., Noble, M. & Seifert, W. Development of oligodendrocytes and Schwann cells studied with a monoclonal antibody against galactocerebroside. Proc. Natl Acad. Sci. USA 79, 2709–2713 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Relvas, J. B. et al. Expression of dominant-negative and chimeric subunits reveals an essential role for β1 integrin during myelination. Curr. Biol. 11, 1039–1043 (2001).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of the ffrench-Constant laboratory for discussions, and L. Decker for advice on neurosphere cultures. This work was supported by the Wellcome Trust and the Multiple Sclerosis Society of Great Britain and Northern Ireland, and by a fellowship from the NIH (to H.C.), a Wellcome Trust research leave fellowship (to C.f.-C.) and a Dutch Multiple Sclerosis Foundation fellowship (to W.B.).

Author information

Authors and Affiliations

  1. Departments of Medical Genetics and Pathology, Center for Brain Repair, University of Cambridge, Cambridge, CB2 2PY, UK

    Holly Colognato, Wia Baron, Jõao B. Relvas & Charles ffrench-Constant

  2. Laboratoire des Pathologies de la Myeline, INSERM, CJF 97-11, Paris, 75634 Cedex 13, France

    Virginia Avellana-Adalid & Anne Baron-Van Evercooren

  3. Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, Illkirch, C.U. de Strasbourg, 67404, France

    Elisabeth Georges-Labouesse

Authors
  1. Holly Colognato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wia Baron
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Virginia Avellana-Adalid
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jõao B. Relvas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anne Baron-Van Evercooren
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Elisabeth Georges-Labouesse
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles ffrench-Constant
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles ffrench-Constant.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colognato, H., Baron, W., Avellana-Adalid, V. et al. CNS integrins switch growth factor signalling to promote target-dependent survival. Nat Cell Biol 4, 833–841 (2002). https://doi.org/10.1038/ncb865

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb865

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing