Abstract

The general wiring of the nervous system is achieved through a sequence of developmental events that include neuronal migration, axon guidance, axonal layer specificity, synaptic specificity and activity-dependent modification of nascent synaptic circuits. Both anatomical and electrophysiological data suggest that certain synaptic connections form between specific synaptic partners at particular subcellular locations from the outset of synaptogenesis. We are exploring the molecular mechanisms that specify synaptic connectivity in C. elegans. To study this question, we have labeled the synapses of 6 different classes of C. elegans neurons with single-cell resolution in vivo and performed genetic analysis on them. These works have led to the identification of two Wnt family proteins that act as negative regulators of synapse formation; a E3 ubiquitin ligase complex that is required for selective synapse elimination; a Netrin/UNC-6—DCC/UNC-40 pathway that coordinates axon guidance and synapse formation in two synaptic partners, thus resulting in the proper formation of a neural circuit and a Netrin/UNC-6—UNC-5 pathway that direct intracellular trafficking of axonal proteins and inhibit synapse formation.

Our data suggest that diverse mechanisms can modulate connectivity and generate specificity at the level of synapse formation.  Synaptic connections can be specified by both positive and negative regulators of synaptogenesis, which can act either via contact-dependent mechanisms or as diffusible molecules. Furthermore, non-neuronal cells such as glial cells play important roles in the assembly of neural circuits. Molecules that appears to pattern synaptic connections are also key molecular cues for axon guidance and morphogenetic cell fate determination.