CNS integrins switch growth factor signalling to promote target-dependent survival.
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.
Colognato
Holly
H
Department of Medical Genetics and Center for Brain Repair, University of Cambridge, Cambridge CB2 2PY, UK.
Baron
Wia
W
Avellana-Adalid
Virginia
V
Relvas
Jõao B
JB
Baron-Van Evercooren
Anne
A
Georges-Labouesse
Elisabeth
E
ffrench-Constant
Charles
C
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002470:Cell Survival; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005109:Extracellular Matrix / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism*; D006579:Heterozygote; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D039503:Integrin alpha6 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009186:Myelin Sheath / Q000378:metabolism; D020880:Neuregulins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors
D006133:Growth Substances; D039503:Integrin alpha6; D016023:Integrins; D008024:Ligands; D020880:Neuregulins; D010980:Platelet Membrane Glycoproteins; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases