The novel Rac effector RIN-1 regulates neuronal cell migration and axon pathfinding inC. elegans

Abstract

SUMMARYCell migration and axon guidance require proper regulation of the actin cytoskeleton in response to extracellular guidance cues. Rho/Rac small GTPases are essential regulators of actin remodeling. Caenorhabditis elegans CED-10 is a Rac1 homolog that is required for various cellular morphological changes and migration events and is under the control of several guidance signaling pathways. There is still considerable uncertainty regarding events following the activation of guidance receptors by extracellular signals and the regulation of actin dynamics based on spatiotemporally restricted Rac activity. Here we show that the VPS9 domain protein RIN-1 acts as a novel effector for CED-10 in C. elegans. The orthologous mammalian Rin1 protein has previously been identified as an effector for Ras GTPase and is now known to function as a guanine nucleotide exchange factor for Rab5 GTPase. We found that RIN-1 specifically binds to the GTP-bound form of CED-10 and that mutations in rin-1 cause significant defects in migration and axon guidance of restricted neuronal cell types including AVM and HSN neurons, in contrast to the various defects observed in ced-10 mutants. Our analyses place RIN-1 in the Slit-Robo genetic pathway that regulates repulsive signaling for dorsoventral axon guidance. In rin-1 mutants, actin accumulated on both the ventral and dorsal sides of the developing HSN neuron, in contrast to its ventral accumulation in wild type. These results strongly suggest that RIN-1 acts as an effector for CED-10/Rac1 and regulates actin remodeling in response to restricted guidance cues.

Distinct CED-10/Rac1 domains confer context-specific functions in development

“…We first focused our analysis on known Rac GTPase interactors. RIN-1 is a VPS9 domain protein that interacts with GTP-bound CED-10 and controls neuronal guidance downstream of Slit-Robo signalling [ 44 ]. We found that RIN-1 is not required for PVQ development and that the penetrance of ced-10(rp100) PVQ defects is not affected by the rin-1(gk431) mutation ( S1 Table ).…”

Rac-GTPases Regulate Microtubule Stability and Axon Growth of Cortical GABAergic Interneurons

“…They are shown to act redundantly in axon pathfinding and migration from Caenorhabditis elegans to mammalian neurons ( Lundquist et al 2001 ; Hakeda-Suzuki et al 2002 ; Luo 2002 ; Ng et al 2002 ; Lundquist 2003 ; Gonzalez-Billault et al 2012 ). A significant degree of conservation among species is also observed in Rac interactors ( Demarco et al 2012 ; Doi et al 2013 ; Law et al 2013 ).…”

Regulation of early endosomes across eukaryotes: Evolution and functional homology of Vps9 proteins

“…However, not all Vps9 subfamilies are ancient. RIN proteins are capable of binding Ras, and play roles in cell signaling, migration and adhesion, thereby linking Rab5‐mediated endocytosis and cell signaling . In addition to GEF activity for Rab5, RIN proteins are involved in Ras binding, as well as endocytosis of various signalling molecules at the cell surface.…”