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CNS integrins switch growth factor signalling to promote target-dependent survival
Holly Colognato1, Wia Baron, Virginia Avellana-Adalid
1Department of Medical Genetics and Center for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK.
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 alpha(6) 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.
Insights
Oligodendrocytes use integrin signaling to switch survival pathways, enabling target-dependent selection during central nervous system development. This mechanism explains how growth factors like neuregulin promote cell differentiation and survival.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Growth factors regulate cell proliferation, survival, and differentiation.
- Cell-surface integrins and extracellular matrix interactions modulate growth factor signaling.
Purpose of the Study:
- To investigate the role of alpha(6) integrin in oligodendrocyte survival signaling.
- To elucidate how integrin-ligand interactions influence growth factor responses during neural development.
Main Methods:
- Utilized knockout mice lacking the alpha(6) integrin receptor.
- Analyzed signaling pathways (PI(3)K and MAPK) in response to neuregulin.
- Examined oligodendrocyte differentiation and survival in vivo.
Main Results:
- Oligodendrocytes lacking alpha(6) integrin showed altered neuregulin signaling.
- Integrin-regulated switch shifted neuregulin dependence from PI(3)K to MAPK pathway.
- This switch enhanced oligodendrocyte survival and promoted differentiation.
Conclusions:
- Integrin-regulated signaling provides a mechanism for target-dependent cell selection in the CNS.
- This switch explains the dual role of neuregulin in oligodendrocyte development.
- Growth factors can have stage-specific, opposing effects mediated by integrin signaling.