Signalling and crosstalk of Rho GTPases in mediating axon guidance

Abstract

Axon extension during development of the nervous system is guided by many factors, but the signalling mechanisms responsible for triggering this extension remain mostly unknown. Here we have examined the role of Rho family small guanosine triphosphatases (GTPases) in mediating axon guidance by diffusible factors. Expression of either dominant-negative or constitutively active Cdc42 in cultured Xenopus laevis spinal neurons, at a concentration that does not substantially affect filopodial formation and neurite extension, abolishes the chemoattractive growth cone turning induced by a gradient of brain-derived neurotrophic factor that can activate Cdc42 and Rac in cultured neurons. Chemorepulsion induced by a gradient of lysophosphatidic acid is also abolished by the expression of dominant-negative RhoA. We also show that an asymmetry in Rho kinase or filopodial initiation across the growth cone is sufficient to trigger the turning response and that there is a crosstalk between the Cdc42 and RhoA pathways through their converging actions on the myosin activity essential for growth cone chemorepulsion.

Enhancement of learning and memory after activation of cerebral Rho GTPases

“…Accordingly, human hemizygosity of LIM-domain-containing protein kinase (LIMK), which is activated by p21-activated kinase (PAK), an effector of Rac GTPase, has been associated with MR (23). On the other hand, Rho activation has been shown to cause neurite retraction (39,40) by means of formation of stress fibers in the growth cone (41) and to reduce growth cone mobility and dendrite branching (42,43). The meaning of these latter actions in the physiology of learning is unclear.…”

RhoA/ROCK Signaling Suppresses Hypertrophic Chondrocyte Differentiation

“…Examples include neuron outgrowth (81,82) and myoblast differentiation (83). The p38 mitogen-activated protein kinases are important effectors of Rac1/Cdc42 (84,85).…”

Ca2+-Dependent Regulation of Rho GTPases Triggers Turning of Nerve Growth Cones

“…The final concentration of cDNAs for injection is 0.2 g/l for DN-Cdc42 or CA-Cdc42 and 0.5 g/l for DN-RhoA and GFP. Approximately 1.5 ng of DN-Cdc42 or CA-Cdc42 and 4 ng of DN-RhoA or enhanced GFP were injected into one of the blastomeres of Xenopus embryos at the two-cell or four-cell stage using an Eppendorf (Hamburg, Germany) transjector 5246, as described previously (Yuan et al, 2003). The embryos were kept in 10% Ringer's solution at room temperature (20 -22°C) for 24 h before preparation of the culture.…”

“…The Rho family of small GTPases may serve as "molecular switches" to regulate the cytoskeletal rearrangements involved in many forms of cell motility (Etienne-Manneville and Hall, 2002). Many factors that influence axon growth, including slits, semaphorins, ephrins, netrins, neurotrophins, MAG, and Nogo, are known to regulate intracellular activity of Rho GTPases (Wahl et al, 2000;Whitford and Ghosh, 2001;Wong et al, 2001;Li et al, 2002;Wang et al, 2002;Yuan et al, 2003), and the perturbation of the activity of Rho GTPases in vivo (Dickson, 2001) or in vitro (Yuan et al, 2003) leads to axon pathfinding defects. Because Cdc42/Rac positively regulate axon extension and stabilization, whereas RhoA increases the tendency of growth cone retraction, it is likely that an activity gradient of Cdc42/Rac across the growth cone triggered by extracellular guidance cues results in preferential axon extension toward the side of higher Cdc42/Rac activity, whereas higher RhoA activity results in preferential retraction of filopodia and repulsive growth cone turning.…”