The long-term objective of this proposal is to understand how genes specify the structure, functioning and development of a behavioral system. Toward this end, the anatomically simple egg-laying system of the nematode Caenorhabditis elegans will be analyzed. Mutants abnormal in egg laying will be used to define both cells that act in egg laying and genes that control the development and functioning of those cells. Four distinct components of the egg-laying system will be analyzed: the vulva (through which eggs are laid); the egg-laying musculature; the nerve cells that directly control the egg-laying musculature; and nerve cells that indirectly regulate egg laying. Vulval development provides an excellent model for both intercellular signaling (how cells communicate) and morphogenesis (how cells generate complex three-dimensional structures). The studies of intercellular signaling in vulval development should reveal the normal biological functions and interactions of genes with human counterparts responsible for cancer. The studies of vulval morphogenesis focus on genes that are involved in the synthesis of specific carbohydrates and that appear to be similar to human genes involved in connective tissue disorders and aging. The contraction of muscles in general and of the C. elegans egg-laying muscles in particular requires the movement of ions through channels that span muscle membranes. The studies of the egg-laying musculature focus on a new class of ion channels and promise to establish new biological roles for ion channels and suggest candidate genes for diseases in which such channels are abnormal. Studies of the two classes of nerve cells (HSNs and VCs) that innervate the egg-laying muscles should help establish molecular genetic mechanisms responsible for many features of nerve cell development and activity, including the determination of cell identity, the outgrowth and branching of processes, and the formation and functioning of synapses (which allow communication between a nerve cell and its targets). Many genes involved in the development of these nerve cells have human counterparts associated with disease. Finally, nerve cells that control both egg laying and other behaviors, e.g., locomotion, will be identified and analyzed based on their effects on how the animal modulates its behavior in response to its environment and experience. Some of these cells communicate using the neurotransmitter serotonin, the target of major pharmaceutical agents used to treat depression -- Prozac, Paxil and Zoloft. In addition, how the environment and experience modulate behavior is a fundamental problem in neuroscience, and these studies should establish cellular and molecular mechanisms responsible for how sensory stimuli regulate behavior and how information about past experience is stored and retrieved.
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