Rho GTPases, dendritic structure, and mental retardation

Abstract

A consistent feature of neurons in patients with mental retardation is abnormal dendritic structure and/or alterations in dendritic spine morphology. Deficits in the regulation of the dendritic cytoskeleton affect both the structure and function of dendrites and synapses and are believed to underlie mental retardation in some instances. In support of this, there is good evidence that alterations in signaling pathways involving the Rho family of small GTPases, key regulators of the actin and microtubule cytoskeletons, contribute to both syndromic and nonsyndromic mental retardation disorders. Because the Rho GTPases have been shown to play increasingly well-defined roles in determining dendrite and dendritic spine development and morphology, Rho signaling has been suggested to be important for normal cognition. The purpose of this review is to summarize recent data on the Rho GTPases pertaining to dendrite and dendritic spine morphogenesis, as well as to highlight their involvement in mental retardation resulting from a variety of genetic mutations within regulators and effectors of these molecules.

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 .…”

Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis

“…REPS2 is associated with a small G protein and shows strong expression in brain tissue (LSBM, http://www.lsbm.org/index.html). As alterations in signaling pathways involving the Rho family of small GTPases contribute to both syndromic and nonsyndromic MR disorders 36 and mutation in the small GTPase gene RAB39B (OMIM300774) were identified in two MR patients, 37 it is possible that deregulated expression of REPS2 contributes to MR. Protein-truncation mutations in NHS have been identified in patients with Nance-Horan syndrome (OMIM 302350), an X-linked developmental disorder characterized by congenital cataracts, dental anomalies, facial dysmorphism and MR in some cases. As our patients in both families did not have cataracts or dental anomalies, the genomic rearrangement involved in NHS may not affect the function of this gene.…”

Rho-linked genes and neurological disorders

“…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. 1).…”