Rap2 and TNIK control Plexin-dependent tiled synaptic innervation in <i>C. elegans</i>.

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 (<i>rap-2</i>) and its effector, TNIK (<i>mig-15</i>), act genetically downstream of Plexin (<i>plx-1</i>) to restrict presynaptic assembly and to form tiled synaptic innervation in <i>C. elegans</i>. Both constitutively GTP- and GDP-forms of <i>rap-2</i> mutants exhibit synaptic tiling defects as <i>plx-1</i> 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 <i>mig-15</i> mutants causes a severe synaptic tiling defect. Conversely, overexpression of <i>mig-15</i> strongly inhibited synapse formation, suggesting that <i>mig-15</i> 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.