DEVELOPMENT Integrins Flip an Oligodendrocyte Switch

Growth factors can mediate different effects on the same populations of cells at different stages of development. For example, platelet-derived growth factor (PDGF) and neuroregulin-1 (NRG) promote proliferation and inhibit the differentiation of oligodendrocyte precursor cells, but they promote survival at the point that oligodendrocytes cease dividing and become terminally differentiated. Contact with axonal targets is also required for the survival of maturing oligodendrocytes. Colognato et al. used transgenic mice lacking the 6 integrin receptor for laminins, in combination with oligodendrocyte culture on different substrata, to investigate the interaction between target-derived cues and the response to growth factors. Mice lacking 6 integrin had fewer myelinating oligodendrocytes than wild-type littermates and showed increased apoptosis. By culturing wild-type neonatal oligodendrocytes on different substrata, the authors determined that cells grown on laminin showed increased survival in response to NRG compared with cells grown on polylysine or fibronectin. Pharmacological analysis with inhibitors of the phosphatidylinositol 3-kinase (PI3K) pathway indicated that NRG-mediated survival of cells grown on polylysine depended upon PI3K signaling, whereas NRG-mediated survival of cells grown on laminin was independent of PI3K signaling. Rather, NRG-mediated survival of oligodendrocytes grown on laminin depended upon activation of mitogen-activated protein kinase (MAPK) pathways, which resulted in increased phosphorylation (inactivation) of the proapoptotic protein BAD. Growing cells on laminin also attenuated the ability of NRG to inhibit oligodendrocyte differentiation. These results provide a mechanism whereby contact with target-associated laminin could switch the effects of NRG to permit terminal differentiation and to promote survival of oligodendrocytes that reach their appropriate axonal targets.

H. Colognato, W. Baron, V. Avellana-Adalid, J. B. Relvas, A. Baron-Van Evercooren, E. Georges-Labouesse, C. ffrench-Constant, CNS integrins switch growth factor signalling to promote target-derived survival. Nature Cell Biol. 11, 833-841 (2002). [Online Journal]