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Molecular Mechanisms of Neural Circuit Development by Gap Junction Networks: Developing neurons in the vertebrate spinal cord, retina, and cortex are interconnected by gap junctions, intercellular channels that allow the direct transfer of electrical signals and small molecules between coupled cells. The functional consequences of these interactions by gap junctions are only partly understood. It remains a challenge to directly address biological roles of gap junctions in the complex nervous system of vertebrates. The nematode C. elegans is an attractive model organism for studies of neuronal gap junction network formation and function because of the simplicity of its nervous system and its experimental accessibility to genetic, molecular, and behavioral manipulations. In particular, classical genetics and reverse genetics (RNA interference) in C. elegans provide powerful methods for identifying genes involved in neuronal development and function. Their transparent cuticles make C. elegans an excellent system for cell biological analyses using live imaging. The nervous system of the hermaphrodite consists of just 302 neurons with characteristic positions, process morphologies, and synaptic connections. Our recent study has demonstrated that the innexin gap junction protein NSY-5 forms a transient embryonic neural network that is essential for establishing left-right asymmetry in olfactory sensory neurons (Chuang et al., Cell, 2007). Communication between cells in this nsy-5-dependent network coordinates distinct patterns of odorant receptor expression on the left and right sides of the olfactory system, leading to long-lasting changes in neuronal function. Our results have uncovered novel roles of gap junctions in neuronal network formation and function. However, little is known about how NSY-5 forms functional channels, how the nsy-5 gap junction network mediates intercellular communication, and how this brief embryonic communication translates into a permanent change that lasts for the rest of the animal's life. We will address these important biological questions using a multidisciplinary approach that integrates molecular genetics, electrophysiology, and cell biology. Future study will determine the structure-function relationship of NSY-5 channels. We will also test the hypothesis that the nsy-5 gap junction network mediates the propagation of small signaling molecules such as calcium and regulates the patterns of later-formed chemical synapses to establish stable left-right neuronal asymmetry. (The Chuang lab is located at R3024, Research Foundation Building. For more information, please contact Dr.Chiou-Fen Chuang, 513-803-0046, chiou-fen.chuang@cchmc.org).

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