Regulating actin dynamics in neuronal growth genes by ADF/cofilin and Rho family GTPases

Growth cone motility and navigation in response to extracellular signals ar e regulated by actin dynamics. To better understand actin involvement in th ese processes me determined how and in what form actin reaches growth cones , and once there, how actin assembly is regulated. A continuous supply of a ctin is maintained at the axon tip by slow transport, the mobile component consisting of an unassembled form of actin, Actin is co-transported with ac tin-binding proteins, including ADF and cofilin, structurally related prote ins essential for rapid turnover of actin filaments in vivo. ADF and cofili n activity is regulated through phosphorylation by LIM kinases, downstream effecters of the Rho family of GTPases, Cdc42, Rac and Rho. Attractive and repulsive extracellular guidance cues might locally alter actin dynamics by binding specific GTPase-linked receptors, activating LIM kinases, and subs equently modulating the activity of ADF/cofilin. ADF is enriched in growth cones and is required for neurite outgrowth. In addition, signals that infl uence growth cone behavior alter ADF/cofilin phosphorylation, and overexpre ssion of ADF enhances neurite outgrowth. Growth promoting effects of lamini n are mimicked by expression of constitutively active Cdc42 and blocked by expression of the dominant negative Cdc42. Repulsive effects of myelin and sema3D on growth cones are blocked by expression of constitutively active R ac1 and dominant negative Rac1, respectively. Thus a series of complex path ways must exist for regulating effecters of actin dynamics. The bifurcating nature of the ADF/cofilin phosphorylation pathway may provide the integrat ion necessary for this complex regulation. (C) 2000 John Wiley & Sons, Inc.