Rho GTPases

Abstract

Ras-homologous guanosine triphosphatases (Rho GTPases) are molecular switches that control the dynamics of the cytoskeleton and mediate the effects of multiple signals that regulate the growth and development of dendrites, dendritic spines, and axons. Mutations affecting Rho GTPase signaling are an important cause of mental retardation. These topics have been the subject of several excellent reviews.1–3 Some of the most salient concepts of the role of Rho GTPases in control of dendritic and axonal growth will be briefly summarized here because of their potential therapeutic implications. For example, inhibition of some Rho GTPase pathways may promote axonal regeneration in spinal cord injury.4–6 The Rho GTPases include at least 23 signaling proteins encoded by 21 different genes in humans. The best characterized are members of the RhoA, Rac, and Cdc42 families.8 These proteins are key regulators of the dynamics of the cytoskeleton, which is required to establish cell polarity and regulate growth and development of dendrites and axons. Rho GTPases function as binary molecular switches between an inactive GDP-bound state and an active GTP-bound state (figure 1). Guanine nucleotide exchange factors facilitate the transition from the inactive GDP-bound to the active GTP-bound state, whereas guanine nucleotide dissociation inhibitors and GTPase activator proteins act as negative regulators of Rho GTPase signaling. Several stimuli, including neurotransmitters, growth factors, and guidance molecules, regulate the growth and development of axons and dendrites via different Rho GTPases. The downstream transduction pathways triggered by these Rho GTPases are complex, and their coordinated activity regulates the dynamics of the actin cytoskeleton and microtubule organization.1,3,8 Figure 1. Mechanisms of activation of Ras-homologous guanosine triphosphatases (Rho GTPases), some of their downstream pathways, and effects on cytoskeleton and neurite growth. The Rho GTPases are activated by guanine nucleotide exchanging factors (GEFs) and inhibited by guanine dissociation inhibitors …