Distinct roles for the two Rho GDP/GTP exchange factor domains of kalirin in regulation of neurite growth and neuronal morphology.

The actin cytoskeleton, essential for neuronal development, is regulated in part by small GTP binding proteins of the Rho subfamily. Kalirin-9, with two Rho subfamily-specific GDP/GTP exchange factor (GEF) domains, localizes to neurites and growth cones of primary cortical neurons. Kalirin-9 overexpression in cultured cortical neurons induces longer neurites and altered neuronal morphology. Expression of the first GEF domain alone results in drastically shortened axons and excessive growth cones, mediated by Rac1. Expression of the second GEF domain alone induces axonal over-elongation and abundant filopodial neurites, mediated by RhoA. Coordination of the actions of the individual GEF domains through their presence in Kalirin-9, with its Sec14p, spectrin, and Src homology domain 3 motifs, is essential for regulating neurite extension and neuronal morphology.