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Throughout life, stem cells in the ventricular-subventricular zone generate neuroblasts that migrate via the rostral migratory stream (RMS) to the olfactory bulb, where they differentiate into local interneurons. Although progress has been made toward identifying extracellular factors that guide the migration of these cells, little is known about the intracellular mechanisms that govern the dynamic reshaping of the neuroblasts' morphology required for their migration along the RMS. In this study, we identify DOCK7, a member of the DOCK180-family, as a molecule essential for tangential neuroblast migration in the postnatal mouse forebrain. DOCK7 regulates the migration of these cells by controlling both leading process (LP) extension and somal translocation via distinct pathways. It controls LP stability/growth via a Rac-dependent pathway, likely by modulating microtubule networks while also regulating F-actin remodeling at the cell rear to promote somal translocation via a previously unrecognized myosin phosphatase-RhoA-interacting protein-dependent pathway. The coordinated action of both pathways is required to ensure efficient neuroblast migration along the RMS., (© 2017 Nakamuta et al.)

The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements in the ventricular zone, to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, actomyosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play critical roles in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration., (Copyright © 2010 Wiley Periodicals, Inc.)

Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3% of children and young adults. Many forms of MR are associated with abnormalities in dendritic structure and/or dendritic spine morphology. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to underlie or contribute to the cognitive disabilities associated with MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. Significantly, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotrophic lateral sclerosis (ALS). Here, we will discuss Rho GTPase-related genes and their signaling pathways involved in MR and ALS.

The formation and elaboration of axonal and dendritic morphologies are fundamental aspects of neuronal polarization critical for information processing. In general, developing CNS neurons elaborate one axon and multiple dendrites in response to intracellular and extracellular cues, so as to transmit and receive information, respectively. The molecular mechanisms underlying axon-dendrite polarity are complex and involve the integration of numerous signaling pathways that impinge on the cytoskeleton. One group of proteins, the Rho GTPases, has emerged as key integrators of environmental cues to regulate the underlying axonal and dendritic cytoskeletons. Here, we discuss the role of regulators of the Rac1 GTPase in axon development and highlight the importance of both actin and microtubule remodeling in this process.

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., (Copyright 2005 Wiley Periodicals, Inc.)

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.

The high incidence of overexpression of some members of the Rho family of GTPases in human tumors suggests that (1) these proteins are involved in cancer onset, and (2) they are potential candidates for a therapeutic intervention. In recent years, the characterization of downstream effectors to Rho GTPases has provided crucial clues on the general cellular effects that permit aberrant proliferation and adhesiveness of tumor cells. The activation of many of these effector proteins in turn results in the modulation of the activity of several transcription factors that play an important role at various levels of Rho signaling. The precise mechanisms by which Rho GTPases participate in carcinogenesis are still not fully understood. However, it is becoming more evident that the specific role of Rho overexpression in tumor initiation, progression and metastasis, as well as the nature and cause of such overexpression in specific human tumors (i.e., transient or stable; tumor environment-regulated; genetic or epigenetic) may be linked to the activation of specific signaling pathways that result in transcriptional regulation. In this review, we summarize the functions of Rho proteins in the regulation of several transcription factors and their relationship to tumor biology.

Dendritic morphology has an important influence on neuronal information processing. Multiple environmental cues, including neuronal activity, the neurotrophin family of growth factors, and extracellular guidance molecules have been shown to influence dendritic size, shape, and development. The Rho GTPases have emerged as key integrators of these environmental cues to regulate the underlying dendritic cytoskeleton.

The functionality and efficacy of Rho GTPase signaling is pivotal for a plethora of biological processes. Due to the integral nature of these molecules, the dysregulation of their activities can result in diverse aberrant phenotypes. Dysregulation can, as will be described below, be based on an altered signaling strength on the level of a specific regulator or that of the respective GTPase itself. Alternatively, effector pathways emanating from a specific Rho GTPase may be under- or overactivated. In this review, we address the role of the Rho-type GTPases as a subfamily of the Ras-superfamily of small GTP-binding proteins in the development of various disease phenotypes. The steadily growing list of genetic alterations that specifically impinge on proper Rho GTPase function corresponds to pathological categories such as cancer progression, mental disabilities and a group of quite diverse and unrelated disorders. We will provide an overview of disease-rendering mutations in genes that have been positively correlated with Rho GTPase signaling and will discuss the cellular and molecular mechanisms that may be affected by them.

The acquisition of a motile and invasive phenotype is an important step in the development of tumors and ultimately metastasis. This step requires the abrogation of cell-cell contacts, the remodeling of the extracellular matrix and of cell-matrix interactions, and finally the movement of the cell mediated by the actin cytoskeleton. Evidence for participation of Rho GTPases in migration and invasion is addressed in this review with emphasis on epithelial cells and the contribution of Rho GTPases toward tumor invasion. The Rho GTPases, including Rac, Cdc42, and Rho, have been implicated in the establishment of cell-cell contacts and of cell-matrix interactions crucial to attaining a fully polarized epithelial state, and they are known for their regulation of the actin cytoskeleton and transcriptional activation. Under aberrant conditions, however, they have been implicated in motility, invasion, and some aspects of metastasis. It is well known that Rho GTPases are activated by different classes of transmembrane receptors and that they transmit these signals to their effector proteins. These downstream targets include not only adaptor proteins and kinases which affect the actin cytoskeleton, but also transcription factors leading to expression of genes necessary for the drastic morphological changes which accompany these processes., (Copyright 2000 Academic Press.)

The development and structural plasticity of dendritic arbors are governed by several factors, including synaptic activity, neurotrophins and other growth-regulating molecules. The signal transduction pathways leading to dendritic structural changes are unknown, but likely include cytoskeleton regulatory components. To test whether GTPases regulate dendritic arbor development, we collected time-lapse images of single optic tectal neurons in albino Xenopus tadpoles expressing dominant negative or constitutively active forms of Rac, Cdc42 or RhoA. Analysis of images collected at two-hour intervals over eight hours indicated that enhanced Rac activity selectively increased branch additions and retractions, as did Cdc42 to a lesser extent. Activation of endogenous RhoA decreased branch extension without affecting branch additions and retractions, whereas dominant-negative RhoA increased branch extension. Finally, we provide data suggesting that RhoA mediates the promotion of normal dendritic arbor development by NMDA receptor activation.

GDP-dissociation inhibitors (GDIs) play a primary role in modulating the activation of GTPases and may also be critical for the cellular compartmentalization of GTPases. RhoGDI and GDI/D4 are two currently known GDIs for the Rho-subfamily of GTPases. Using their cDNAs to screen a human brain cDNA library under low stringency, we have cloned a homologous cDNA preferentially expressed at high levels in brain and pancreas. The predicted protein, named RhoGDIgamma, is approximately 50% identical to GDI/D4 and RhoGDI. It binds to CDC42 and RhoA with less affinity compared with RhoGDI and does not bind with Rac1, Rac2, or Ras. RhoGDIgamma functions as a GDI for CDC42 but with approximately 20 times less efficiency than RhoGDI. Immunohistochemical studies showed a diffuse punctate distribution of the protein in the cytoplasm with concentration around the nucleus in cytoplasmic vesicles. Overexpression of the protein in baby hamster kidney cells caused the cells to round up with loss of stress fibers. A distinct hydrophobic amino terminus in RhoGDIgamma, not seen in the other two RhoGDIs, could provide a mechanism for localization of the GDI to specific membranous compartment thus determining function distinct from RhoGDI or GDI/D4. Our results provide evidence that there is a family of GDIs for the Rho-related GTPases and that they differ in binding affinity, target specificity, and tissue expression. We propose that RhoGDI be renamed RhoGDIalpha and GDID4 be renamed RhoGDIbeta. The new GDI should widen the scope of investigation of this important class of regulatory protein.