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

Colognato, Holly, Baron, Wia, Avellana-Adalid, Virginia, Relvas, Jõao B., Baron-Van Evercooren, Anne, Georges-Labouesse, Elisabeth and ffrench-Constant, Charles ORCID: (2002) CNS integrins switch growth factor signalling to promote target-dependent survival. Nature Cell Biology, 4 (11). pp. 833-841. ISSN 1465-7392

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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.

Item Type: Article
Additional Information: Funding Information: 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.). Correspondence and requests for materials should be addressed to C.f.-C.
Uncontrolled Keywords: cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1307
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 16 Jul 2022 13:30
Last Modified: 14 Jul 2024 01:23
DOI: 10.1038/ncb865

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