We will continue our Program Project to learn the mechanisms of cell signaling, specification and commitment during embryonic development. We propose three component projects, each addressing one of these three issues. We will carry out these studies in the zebrafish, Brachydanio rerio, because of the advantages it offers as an experimental system, including labeling and transplanting single cells, genetic analysis of developmental pathways, and production of transgenic animals. Specifically, we propose to examine induction of the nervous system and the development of two cell lineages -- primary neurons that form the earliest neural circuitry in the embryo and neural crest cells that form the peripheral nervous system and structures in the head and heart. Induction of these lineages involves cell signaling by inducing (growth/survival) factors, and their receptors, and depends on cell position in the embryo. Before overt differentiation, cells become specified. While these specifications may involve phenotypic changes, they do not represent irreversible commitments that restrict the cells to a single developmental course. We propose to examine whether these """"""""conditional"""""""" specifications are temporally separable from commitment in neuronal and neural crest lineages. Our main long-term objectives are to identify the regulatory molecules and their genes that underlie signaling, specification and commitment during vertebrate development, and to discover their functional interactions. Disruption of such mechanisms during development of the human central and peripheral nervous systems results in numerous diseases or syndromes, including (a) hereditary dysplasias and neuropathies such as Familial Dysautonomia, Hirschprung's disease (aganglionic megacolon), and orthostatic hypotension; (b) hereditary metaplasias, such as von Recklinghausen's disease (Neurofibromatosis); (c) numerous neoplasias, such as gliomas, neuroblastomas, and pheochromocytomas; and (d) congenital defects such as spina bifida, cleft lip/palate, and craniofacial defects associated with heart malformation (e.g. Pierre Robin syndrome). A detailed understanding of the regulatory mechanisms of normal neural development in vertebrates embryos will help elucidate such disease processes.
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