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 t wo Rho subfamily-specific GDP/GTP exchange factor (GEF) domains, localizes to neurites and growth cones of primary cortical neurons. Kalirin-9 overexp ression in cultured cortical neurons induces longer neurites and altered ne uronal morphology. Expression of the first GEF domain alone results in dras tically shortened axons and excessive growth cones, mediated by Rac1. Expre ssion of the second GEF domain alone induces axonal over-elongation and abu ndant filopodial neurites, mediated by RhoA. Coordination of the actions of the individual GEF domains through their presence in Kalirin-9, with its S ec14p, spectrin, and Src homology domain 3 motifs, is essential for regulat ing neurite extension and neuronal morphology.