Interaxonal Interaction Defines Tiled Presynaptic Innervation in C. elegans

Abstract

Summary Cellular interactions between neighboring axons are essential for global topographic map formation. Here we show that axonal interactions also precisely instruct the location of synapses. Motoneurons form en passant synapses in Caenorhabditis elegans. While axons from the same neuron class significantly overlap, each neuron innervates a unique and tiled segment of the muscle field by restricting its synapses to a distinct subaxonal domain—a phenomenon we term “synaptic tiling”. Using DA8 and DA9 motoneurons as a model, we found that the synaptic tiling requires Plexin(PLX-1) and two transmembrane Semaphorins. In the Plexin or Semaphorin mutants, synaptic domains from both neurons expand and overlap with each other without guidance defects. In a Semaphorin-dependent manner, PLX-1 is concentrated at the synapse-free axonal segment, delineating the tiling border. Furthermore, Plexin inhibits presynapse formation by suppressing synaptic F-actin through its cytoplasmic GAP domain. Hence, contact-dependent, intra-axonal Plexin signaling specifies synaptic circuits by inhibiting synapse formation at the subcellular loci.

Genetic dissection of plexin signaling in vivo

“…Surprisingly, although plexins have been shown to regulate several independent signaling pathways in vitro, mutations in the GAP domain were sufficient to fully phenocopy the null mutants in vivo with respect to development of the nervous, the vascular, and the skeletal system. This crucial importance of the GAP domain of plexins during mouse development is in line with findings in Drosophila and Caenorhabditis elegans, where the GAP domains of PlexA and PLX-1 have been shown to be critical for development of the nervous system (47,48). Owing to the perinatal lethality of Plexin-B2 and Plexin-D1 GAP domain mutant mice, we could not systematically address the functional significance of the GAP domain at postnatal stages of development or in physiological and pathophysiological processes in the adult [e.g., for Plexin-B2 in the postnatal migration and proliferation of neuroblasts (26) and in wound healing (49), or for Plexin-D1 in postnatal development of the nervous system (34,35) and in angiogenesis (36,50)].…”

Semaphorins and their Signaling Mechanisms

“…For example, cis (on the same cell) binding between semaphorins and plexins inhibits the binding of Semas/plexins in trans (on different cells), thereby suppressing intercellular signaling (76–78). Cis binding also appears to activate plexin signaling in cis (79). Second, transmembrane Semas can act as receptors (“reverse signaling”; reviewed in (45,46)).…”

Semaphorins and the dynamic regulation of synapse assembly, refinement, and function

“…In C. elegans two transmembrane semaphorins, Sema-1 and Sema-2, which signal through the plexin-1 receptor, act to restrict en passant synapse formation between complementary axonal regions of two adjacent motor neurons and the same muscle field [17••]. Further, in the mouse cerebral cortex the secreted semaphorin Sema3F regulates subcellular synapse specificity by constraining dendritic spine density selectively along apical dendrites of deep layer pyramidal neurons [8] (Figure 1a).…”