Abstract
UNC-6/Netrin is a conserved axon guidance cue that directs growth cone migrations in the dorsal-ventral axis of C. elegans and in the vertebrate spinal cord. UNC-6/Netrin is expressed in ventral cells, and growth cones migrate ventrally toward or dorsally away from UNC-6/Netrin. Recent studies of growth cone behavior during outgrowth in vivo in C. elegans have led to a polarity/protrusion model in directed growth cone migration away from UNC-6/Netrin. In this model, UNC-6/Netrin first polarizes the growth cone via the UNC-5 receptor, leading to dorsally biased protrusion and F-actin accumulation. UNC-6/Netrin then regulates protrusion based on this polarity. The receptor UNC-40/DCC drives protrusion dorsally, away from the UNC-6/Netrin source, and the UNC-5 receptor inhibits protrusion ventrally, near the UNC-6/Netrin source, resulting in dorsal migration. UNC-5 inhibits protrusion in part by excluding microtubules from the growth cone, which are pro-protrusive. Here we report that the RHO-1/RhoA GTPase and its activator GEF RHGF-1 inhibit growth cone protrusion and MT accumulation in growth cones, similar to UNC-5. However, growth cone polarity of protrusion and F-actin were unaffected by RHO-1 and RHGF-1. Thus, RHO-1 signaling acts specifically as a negative regulator of protrusion and MT accumulation, and not polarity. Genetic interactions are consistent with RHO-1 and RHGF-1 acting with UNC-5, as well as with a parallel pathway, to regulate protrusion. The cytoskeletal interacting molecule UNC-33/CRMP was required for RHO-1 activity to inhibit MT accumulation, suggesting that UNC-33/CRMP might act downstream of RHO-1. In sum, these studies describe a new role of RHO-1 and RHGF-1 in regulation of growth cone protrusion by UNC-6/Netrin.
Highlights
The connectivity of neuronal circuits is established through properly guided axons which form functional synaptic connections
Loss of rho-1 leads to embryonic lethality, with a failure in cytokinesis [38], and perturbation of RHO-1 signaling in adults results in dysfunction in numerous neuronal and non-neuronal functions leading to death [39]
Growth cone area was increased, but not significantly so. These results indicate that RHO-1 activity inhibits growth cone protrusion
Summary
The connectivity of neuronal circuits is established through properly guided axons which form functional synaptic connections. The prevailing model of UNC-6/Netrin-mediated axon guidance involves a ventral-to-dorsal chemotactic gradient of the molecule, which growth cones interpret by migrating up or down the gradient using the “attractive” receptor UNC-40/DCC or the “repulsive” receptor UNC-5, respectively [12, 13]. This model has recently been challenged by studies in mouse spinal cord showing that floorplate Netrin is dispensable for commissural axon guidance, and that ventricular expression is important, possibly in a close-range, haptotactic event [14,15,16,17]
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