Diverse roles of Rho family GTPases in neuronal development, survival, and death

Abstract

Rho family GTPases (eg., RhoA, Rac1 and Cdc42) are monomeric G-proteins that act as key transducers of extracellular signals to the actin cytoskeleton. In the nervous system, Rho family GTPases are essential regulators of neuronal growth cone motility, axonal migration, and dendritic spine morphogenesis. Given these vital functions, it is perhaps not surprising that mutations in several proteins involved in Rho GTPase signaling are causative in some forms of mental retardation. In addition, numerous recent studies have identified Rho family GTPases as central players in the molecular pathways that determine neuronal survival and death. Interestingly, individual Rho family members have been shown to play either a pro-death or pro-survival role in the nervous system depending on both the type of neuron and the particular neurodegenerative insult involved. This review summarizes current work demonstrating a critical role for Rho family GTPases and their effectors in the regulation of neuronal development, survival, and death. These findings may be particularly relevant in the context of specific neurodegenerative disorders in which Rho family GTPase function is altered, such as loss-of-function of the Rac1 guanine nucleotide exchange factor, alsin, in juvenile-onset amyotrophic lateral sclerosis.