Functional and developmental regulation of cholinergic synapses in C. elegans by the Ror receptor tyrosine kinase CAM-1. Michael M. Francis , Susan P. Evans, David M. Madsen, Andres V. Maricq. Biology, University of Utah, Salt Lake City, UT.

The development and functional regulation of synapses involves the concerted activity of numerous pre- and post-synaptic elements whose expression and localization must be tightly regulated. With a few exceptions, little is known about the molecular events leading to synapse formation and stabilization of the synaptic architecture. The C. elegans neuromuscular junction (NMJ) is composed of both GABAergic and cholinergic synapses. Thus, study of the C. elegans NMJ provides a unique opportunity to identify key molecules involved in regulating the synapses of a polyinnervated cell. The Ror receptor tyrosine kinase CAM-1 is expressed at the C. elegans NMJ and a deletion mutation in the cam-1 gene results in uncoordinated movement. We have analyzed the morphology and function of neuromuscular synapses in cam-1(ak37) worms using pre- and post-synaptic GFP markers as well as electrophysiology. Mutation of the cam-1 gene appears to selectively affect the development and function of cholinergic synapses. Specifically, the distribution of cholinergic synaptic vesicles is selectively altered (as visualized using unc-4 ::VAMP::GFP) and cholinergic responses to both nerve-evoked and drug-evoked stimulation are impaired. Interestingly, GABAergic neurotransmission appears unaffected by the cam-1(ak37) mutation. These deficits in synaptic function can be rescued in worms expressing a full-length CAM-1::GFP transgene. Furthermore, we have undertaken domain analysis of CAM-1 to determine sequence elements required for rescue. Notably, a transgene encoding a truncated form of CAM-1 that lacks a majority of the intracellular domains (including the kinase domain) is also sufficient for rescue. This result suggests that extracellular domains such as the immunoglobulin domain or kringle domain are important for the function of CAM-1. We propose that CAM-1 participates in the regulation of cholinergic synapses via protein-protein interactions mediated by sequence elements in the extracellular portion of the molecule.

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