Abstract
UNC-6/Netrin is a conserved axon guidance cue that can mediate both attraction and repulsion. We previously discovered that attractive UNC-40/DCC receptor signaling stimulates growth cone filopodial protrusion and that repulsive UNC-40–UNC-5 heterodimers inhibit filopodial protrusion in C. elegans. Here, we identify cytoplasmic signaling molecules required for UNC-6-mediated inhibition of filopodial protrusion involved in axon repulsion. We show that the Rac-like GTPases CED-10 and MIG-2, the Rac GTP exchange factor UNC-73/Trio, UNC-44/Ankyrin and UNC-33/CRMP act in inhibitory UNC-6 signaling. These molecules were required for the normal limitation of filopodial protrusion in developing growth cones and for inhibition of growth cone filopodial protrusion caused by activated MYR::UNC-40 and MYR::UNC-5 receptor signaling. Epistasis studies using activated CED-10 and MIG-2 indicated that UNC-44 and UNC-33 act downstream of the Rac-like GTPases in filopodial inhibition. UNC-73, UNC-33 and UNC-44 did not affect the accumulation of full-length UNC-5::GFP and UNC-40::GFP in growth cones, consistent with a model in which UNC-73, UNC-33 and UNC-44 influence cytoskeletal function during growth cone filopodial inhibition.
Highlights
Extracellular guidance cues are detected by receptors on the growth cone and guide growth cone migration
Our results suggest that CED-10 and MIG-2 are involved in both pro- and antiprotrusive functions in the growth cone and that their roles in each are controlled by distinct guanine nucleotide exchange factor (GEF): UNC-73 in inhibition and TIAM-1 in stimulation (Demarco et al, 2012) of protrusion
We found that in unc-73(rh40) mutants VD growth cones had significant increases in filopodial protrusiveness, exhibiting on average longer filopodia (e.g. 0.96 μm in wild type compared with 1.44 μm in unc-73(rh40); P
Summary
Extracellular guidance cues are detected by receptors on the growth cone and guide growth cone migration. The guidance cue UNC-6/ Netrin and its receptors UNC-5 and UNC-40/DCC control both attraction and repulsion in the dorsal-ventral axis (Chan et al, 1996; Leonardo et al, 1997; Hong et al, 1999; Montell, 1999; Shekarabi and Kennedy, 2002; Moore et al, 2007). *Present address: FAS Center for Systems Biology, Harvard University, 52 Oxford Street, Cambridge, MA 02138, USA.
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