The role of the Rho GTPases in neuronal development

Abstract

Our brain serves as a center for cognitive function and neurons within the brain relay and store information about our surroundings and experiences. Modulation of this complex neuronal circuitry allows us to process that information and respond appropriately. Proper development of neurons is therefore vital to the mental health of an individual, and perturbations in their signaling or morphology are likely to result in cognitive impairment. The development of a neuron requires a series of steps that begins with migration from its birth place and initiation of process outgrowth, and ultimately leads to differentiation and the formation of connections that allow it to communicate with appropriate targets. Over the past several years, it has become clear that the Rho family of GTPases and related molecules play an important role in various aspects of neuronal development, including neurite outgrowth and differentiation, axon pathfinding, and dendritic spine formation and maintenance. Given the importance of these molecules in these processes, it is therefore not surprising that mutations in genes encoding a number of regulators and effectors of the Rho GTPases have been associated with human neurological diseases. This review will focus on the role of the Rho GTPases and their associated signaling molecules throughout neuronal development and discuss how perturbations in Rho GTPase signaling may lead to cognitive disorders.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…RhoGTPases and their regulators, GTPase-activating proteins (GAPs) and guanine-exchange factors (GEFs), are critical mediators of dendritic arborization, spine morphogenesis, growth cone development, axon guidance [240][241][242][243][244][245] and neuronal survival 246 .…”

Rho-linked genes and neurological disorders

“…Rho GTPases, among which Rac1, Cdc42 and RhoA have been most extensively studied, are best known for their effects on the actin cytoskeleton, but more recently they have also been shown to influence microtubule organization [22,33,93]. As key regulators of the cytoskeleton, the Rho proteins have been implicated in different aspects of neuronal morphogenesis, including dendritic arbor development and spine morphogenesis [31]. For instance, Rac1 and Cdc42 have been shown to promote, whereas RhoA to inhibit the growth and/or stability of dendritic spines [77].…”

“…For instance, Rac1 and Cdc42 have been shown to promote, whereas RhoA to inhibit the growth and/or stability of dendritic spines [77]. A number of regulators, as well as effectors that mediate the effects of the Rho GTPases on the actin cytoskeleton and spine morphogenesis have been identified over the past few years [31,60]. The importance of proper Rho GTPase signaling in neuronal development and function has been highlighted by the identification of MR genes that encode regulators and effectors of Rho GTPases such as OPHN1, PAK3, ARHGEF6, FMR1 and MEGAP (Table 1).…”

“…One group of proteins, small GTP-binding proteins of the Rho subfamily, and in particular Rac1, Cdc42 and RhoA GTPases, have emerged as key modulators of dendritic spine morphogenesis through their regulation of actin organization [31]. Hence, it is not surprising that mutations in genes encoding regulators and effectors of the Rho GTPases have been found to underlie human neurological diseases [60,83] (Fig.…”

Isolation and characterization of a novel gene, xMADML, involved in Xenopus laevis eye development

“…Similarly, De Langhe et al (2002) isolated NRBP from a yeast two-hybrid screen for proteins interacting with Rac3, a small GTPase expressed primarily in projecting cells of the nervous system. The Rho-GTPase family of proteins has roles in numerous cellular activities, including cell motility, cytoskeletal arrangement, cell trafficking, and cell growth by regulating actin dynamics, with resultant effects on tissue development and differentiation (reviewed in Van Aelst and D'Souza- Schorey, 1997;Hall, 1998;and Govek et al, 2005). NRBP was also shown to localize to the Golgi apparatus and places of membrane motility, further increasing the likelihood that NRBP plays roles in the control of cell structure or surface membrane composition (Chua et al, 2004).…”