Coupling neurotrophins to cell migration through selective guanine nucleotide exchange factor activation

Myelinating glia provide an insulating sheath around axons that is required for the rapid propagation of axon potentials and normal function of the central and peripheral nervous systems. Myelinated nerve fibers develop in a series of stages. Axons initially grow out largely devoid of glia; they stimulate the generation of immature, premyelinating Schwann cells that migrate along the axon, resulting in a full complement of these glial cells along the length of the nerve fiber. Subsequently, Schwann cells differentiate and elaborate a myelin sheath. This developmental sequence and the intimate apposition of Schwann cells with nerve fibers suggest bidirectional signaling between these cell types mediated by cell adhesion molecules and growth factors and their cognate receptors. The actions of one class of growth factor, the neurotrophins, have been particularly well characterized for effects on premyelinating Schawnn cells. In a body of work spanning the past four years, Shooter and colleagues (1, 2) have demonstrated that locally produced neurotrophin-3 (NT-3) promotes Schwann cell migration by activating the TrkC receptor tyrosine kinase. In contrast, the related neurotrophin, brain-derived neurotrophic factor (BDNF), binds the unrelated p75 receptor to inhibit Schwann cell migration and promote differentiation and myelination (2, 3). A mechanism by which the p75 receptor inhibits Schwann cell migration was previously elucidated by the studies of Yamiuchi et al. (2), whereby p75 couples to the guanine exchange factor Vav2 to activate the RhoA GTPase. A study in a recent issue of PNAS (4) reveals that TrkC promotes Schwann cell migration by using the guanine exchange factor Dbs to activate the Cdc42 GTPase. Collectively, these observations suggest that BDNF and NT3 mediate opposing actions on Schwann cell migration through binding to different receptors, by coupling these receptors to the recruitment of distinct guanine exchange factors, and by the selective activation of …