Abstract
During development, neurons form synapses with their fate-determined targets. While we begin to elucidate the mechanisms by which extracellular ligand-receptor interactions enhance synapse specificity by inhibiting synaptogenesis, our knowledge about their intracellular mechanisms remains limited. Here we show that Rap2 GTPase (rap-2) and its effector, TNIK (mig-15), act genetically downstream of Plexin (plx-1) to restrict presynaptic assembly and to form tiled synaptic innervation in C. elegans. Both constitutively GTP- and GDP-forms of rap-2 mutants exhibit synaptic tiling defects as plx-1 mutants, suggesting that cycling of the RAP-2 nucleotide state is critical for synapse inhibition. Consistently, PLX-1 suppresses local RAP-2 activity. Excessive ectopic synapse formation in mig-15 mutants causes a severe synaptic tiling defect. Conversely, overexpression of mig-15 strongly inhibited synapse formation, suggesting that mig-15 is a negative regulator of synapse formation. These results reveal that subcellular regulation of small GTPase activity by Plexin shapes proper synapse patterning in vivo.
Highlights
During nervous system development, various instructive and repulsive signaling cues cooperatively direct neurons to form chemical synapses with their appropriate targets
RAP-2 activity is spatially regulated by PLX-1 Previously, we demonstrated that PLX-1::GFP is localized at the anterior edge of the DA9 synaptic domain, where it negatively regulates synapse formation through its cytoplasmic GAP domain (Figures 3A and 3E) (Mizumoto and Shen, 2013a)
We discovered the role of Rap2 GTPase and TNIK in synapse pattern formation in C. elegans
Summary
Various instructive and repulsive signaling cues cooperatively direct neurons to form chemical synapses with their appropriate targets. Several axon guidance cues and their receptors play critical roles to inhibit synapse formation (Inaki et al, 2007). Semaphorins (Sema) and their receptors, Plexins, are two conserved families of molecules that have a well-established function to repel axons during development (Kolodkin et al, 1993; 1992; Negishi et al, 2005; Tran et al, 2007) and prominent roles contributing to immune system, cardiovascular development and cancer regulation (Epstein et al, 2015; Neufeld et al, 2005; Takamatsu and Kumanogoh, 2012). In addition to its function as a long-range axon guidance cue during neuronal development, Sema/Plexin signaling plays a critical role as a negative regulator of synapse formation. Little is known about the intracellular mechanisms through which Sema/Plexin signaling inhibits synapse formation
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