Rho and Ras GTPases in Axon Growth, Guidance, and Branching

Abstract

The establishment of precise neuronal cell morphology provides the foundation for all aspects of neurobiology. During development, axons emerge from cell bodies after an initial polarization stage, elongate, and navigate towards target regions guided by a range of environmental cues. The Rho and Ras families of small GTPases have emerged as critical players at all stages of axonogenesis. Their ability to coordinately direct multiple signal transduction pathways with precise spatial control drives many of the activities that underlie this morphogenetic program: the dynamic assembly, disassembly, and reorganization of the actin and microtubule cytoskeletons, the interaction of the growing axon with other cells and extracellular matrix, the delivery of lipids and proteins to the axon through the exocytic machinery, and the internalization of membrane and proteins at the leading edge of the growth cone through endocytosis. This article highlights the contribution of Rho and Ras GTPases to axonogenesis.

Cholesterol 24S-Hydroxylase Overexpression Inhibits the Liver X Receptor (LXR) Pathway by Activating Small Guanosine Triphosphate-Binding Proteins (sGTPases) in Neuronal Cells

“…This mechanism may also be part of the explanation for the cognitive improvement in the AD mice model overexpressing CYP46A1 [17]. Indeed, as above-mentioned sGTPases proteins are involved in the control axon growth, guidance and branching, dendritic spine formation and stabilization, growth cone motility and collapse and synapse formation [29][30][31], and consequently on memory formation, LTP induction and maintenance, and synaptic modulation [31,33,34]. We are currently investigation the full impact of CYP46A1-dependent sGTPases activation, namely in terms of neuronal development and function.…”

“…Rho proteins have been extensively associated with actin cytoskeleton remodeling and are therefore critical to CNS neuronal cell migration, axon growth, guidance and branching, dendritic spine formation and stabilization, growth cone motility and collapse, and synapse formation [29][30][31]. Additionally, Rho GTPases have also been implicated in the correct formation of myelin sheaths [32].…”

“…Additionally, Rho GTPases have also been implicated in the correct formation of myelin sheaths [32]. Ras are involved in axon growth, memory formation, LTP induction and maintenance, and synaptic modulation [31,33,34], while Rab proteins have been mainly associated with endocytosis, synaptic vesicles exocytosis, axonal retrograde transport, and postsynaptic compartment dynamics of glutamate receptors [35]. In accordance to their pivotal role in the CNS, Ras, Rho, and Rab sGTPases have also been implicated in a number of neurological diseases.…”

Initiating and Growing an Axon

“…Not surprisingly, both Ras-and Rho-family small GTPases have been shown to be involved in axon specification and axon growth. We refer the reader to Hall and Lalli (2010) for a comprehensive review of the roles played by small GTPases in the regulation of neuronal morphology.…”

Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton

“…The b-PIX-GIT1 complex interacts with additional scaffolds to yield large dynamic molecular assemblies, which tune the protrusive activity at the cell edge (Asperti et al, 2011). Finally, Rho GTPases cooperate with Ras to regulate axon outgrowth (reviewed by Hall and Lalli, 2010). Furthermore, they cooperate with RalA, a small GTPase of the Ras family that is activated downstream of oncogenic Ras, in the assembly of exocyst components (reviewed by Wu et al, 2008, and see below).…”