The long-term objective of this work is to elucidate the genetic and molecular mechanisms by which neural circuits are assembled in the developing nervous system. The proposed project will analyze how a specific neuromuscular unit in the egg-laying system of the nematode Caenorhabditis elegans is assembled. The nervous system of an animal is a highly ordered collection of neural circuits that control and coordinate the behavior of an animal. To understand how these neural circuits are assembled and how the wiring diagram of the nervous system is determined ultimately depends on understanding how growing axons find their targets and how target cells are positioned into their correct places. This problem of neuronal guidance and target positioning is being addressed in C. elegans, an animal that offers certain experimental advantages. The origin and fate of every somatic cell is known, detailed anatomy and connectivity for all 302 neurons have been described, the entire wiring diagram of the nervous system has been inferred, and the animal is amenable to genetic manipulations. The egg-laying system of C. elegans is accessible and well-defined. The development of each cell type in the system can be selectively perturbed by mutation and/or by ablation with a laser microbeam. Analysis of such perturbed animals has suggested a role for specific cells in the assembly of the egg-laying motor system. The goals of the proposed research are to define further the cells and cell interactions necessary for the guidance of the neuronal processes and the positioning of the muscles in egg-laying. Mutants will be isolated in which these cell interactions are disrupted, these mutations should identify the genes that encode and regulate these processes. The identification of these genes and the functional characterization of their products may disclose how one neuromuscular unit is assembled. The mechanisms elucidated in this system may reveal general mechanisms for assembly of neural circuits not only in C. elegans, but in other organisms as well. These rules may yield insights into how nervous systems become """"""""miswired"""""""" during development in higher organisms.
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