1. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
2. Department of Pharmacology, University of Wisconsin, Madison, Wisconsin 53706, USA
3. Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
4. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
5. †Present address: College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA
6. *These authors contributed equally to this work

Correspondence to: Joshua M. Kaplan^1,4 Correspondence and requests for materials should be addressed to J.M.K. (Email: kaplan@molbio.mgh.harvard.edu).

Abstract

Chemical synapses are complex structures that mediate rapid intercellular signalling in the nervous system. Proteomic studies suggest that several hundred proteins will be found at synaptic specializations. Here we describe a systematic screen to identify genes required for the function or development of Caenorhabditis elegans neuromuscular junctions. A total of 185 genes were identified in an RNA interference screen for decreased acetylcholine secretion; 132 of these genes had not previously been implicated in synaptic transmission. Functional profiles for these genes were determined by comparing secretion defects observed after RNA interference under a variety of conditions. Hierarchical clustering identified groups of functionally related genes, including those involved in the synaptic vesicle cycle, neuropeptide signalling and responsiveness to phorbol esters. Twenty-four genes encoded proteins that were localized to presynaptic specializations. Loss-of-function mutations in 12 genes caused defects in presynaptic structure.

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