CAM-1 function at the C. elegans neuromuscular junction

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DESCRIPTION (provided by applicant): A number of drugs of abuse and therapeutics act by altering the efficacy of synaptic transmission. Likewise, the pathophysiology of many neurological disorders is rooted in synaptic dysfunction. However, the processes that regulate the organization and maintenance of the synaptic architecture remain largely unknown. Receptor tyrosine kinases (RTKs) have been shown to regulate neurite outgrowth and the clustering of post-synaptic neurotransmitter receptors. The C. elegans RTK CAM-1 is related to both Muscle-specific kinase (MUSK), an RTK required for clustering of post-synaptic acetylcholine receptors (AChRs) at the mammalian neuromuscular junction (NMJ), and the mammalian Ror family of RTKs. Ror RTKs are highly conserved across species and are widely expressed in the mammalian nervous system. However, the functional roles of Ror RTKs in the nervous system are unknown. Our preliminary results show that CAM-1 is localized to the C. elegans NMJ and that targeted mutation of the cam-1 gene results in altered synaptic transmission at C. elegans neuromuscular synapses. The experiments in this proposal are designed to test the functional role of CAM-1 at the C. elegans NMJ. We will determine the subcellular distribution of CAM-1 and assess whether it is colocalized with specific neurotransmitter receptors. Furthermore, we will determine if CAM-1 physically interacts with specific synaptic proteins involved in neurotransmission. Finally, to identify potential ligands and downstream effectors for Ror RTKS, we will screen for suppressors of the paralysis caused by overexpression of CAM-1 in C. elegans muscles. This research program will provide novel insights into potential synaptic functions for CAM-1 and Ror kinases in general. The proposed experiments will also provide valuable training for the applicant in C. elegans research techniques. Through a diverse training program including formal lectures, informal presentations and research, the applicant will gain new experience in the design and implementation of C. elegans molecular genetic approaches. These approaches will complement the applicant's previous training in ion channel physiology, ultimately enabling the applicant to direct an independent research program focused upon the biological regulation of synaptic function in C. elegans. The application of genetic techniques in concert with electrophysiological approaches in the Maricq laboratory makes this an ideal location for the proposed training.