This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of these studies is to elucidate the molecular mechanisms that regulate the formation of synaptic contacts. Synapse formation is a well-programmed developmental process involving cell-cell interactions carried out by distinct groups of molecules required for recognition of postsynaptic targets, stabilization of the contact between synaptic membranes, and functional coupling between synaptic compartments. As synapses are the central component of neuronal communication and are disrupted in a variety of mental and neurological disorders, the identification of the molecular mechanisms that participate in the establishment of synaptic connections will contribute to our understanding of the formation of neuronal circuits and the causes of mental and neurological diseases. This proposal focuses on the identification and characterization of proteins capable of inducing synapse formation during embryogenesis. Our central hypothesis is that the expression of membrane tethered or secreted ligands by presumptive postsynaptic neurons is required to induce the differentiation of the presynaptic terminal and the establishment of a synaptic contact. To this aim, we carried out a genome-wide search of genes that become activated during the initiation of synapse development in the intact animal, which led to the identification of a group of proteins having the molecular features of proteins that may participate in the initiation of synapse formation. This two-year project will determine the synaptogenic activity of the identified proteins by using in vitro cell assays to examine their activity on neurite outgrowth and presynaptic terminal differentiation.
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