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. Three distinct components of the egg-laying system will be analyzed: the vulva (through which eggs are laid), the egg-laying musculature, and the nerve cells that either directly or indirectly control the egg-laying musculature and 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 identification of genes that are essential for cell viability only in the absence of one gene important in vulval development - a C. elegans counterpart of the Rb tumor suppressor gene - may well define new therapeutic targets for cancer. The studies of vulval morphogenesis focus on genes that are involved in the synthesis of a specific carbohydrate 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 and mechanisms of regulation of these ion channels and to suggest candidate genes for diseases in which such channels are abnormal. Nerve cells that control the behavior of egg laying and/or other behaviors coordinately regulated with egg laying will be identified and analyzed based on their effects on how the animal modulates it behavior in response to both its environment and experience. Some of these cells communicate using the neurotransmitter serotonin, which in humans modulates mood, sleep, pain, and other physiological processes and is the target of the 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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