Understanding the early development of patterning of the nervous system and its underlying genetic control is essential for progress in the alleviation of genetic-determined mental health disorders, of congenital diseases, and of cancers. In this proposal, Dr. Kimmel proposes to study neural patterning in the small and simple nervous system of the zebrafish embryo. This species has many attributes for both developmental and genetic study, and can serve as a model system for understanding the neural development in all vertebrates, including humans. The proposed experiments address the nature of segmental patterning of the hindbrain and the connections of the hindbrain segments with the jaw and pharyngeal segments of the head periphery.
The specific aims proposed by Dr. Kimmel are as follows: (1) Mutations will be collected and characterized that disrupt the earliest stages of segmental patterning. The genes identified by these mutations might act specifically in the neural plate or in head mesoderm as predicted by alternative hypotheses. Molecular analysis and genetic mosaic analyses will establish in which tissue these early-acting genes function. (2) The fate map positions of functionally interacting cells in the hindbrain and head periphery will be compared. This analysis will test a prediction that at the early stage when segmental identities are specified in the head primordium, the progenitors of particular skeletal components, of muscle cells that insert on these components, and of motoneurons that control this muscle are precisly aligned in the head fate map. (3) The cellular basis of hindbrain and pharyngeal arch segment formation will be analyzed. Methods for cell lineage analysis and for time-lapse analyses of morphogenesis in vivo will be used to examine predictions that segments develop as lineage-restricted compartments, and to learn when segment borders form. Transplantation of single identified postmitotic young neurons in the early brain segments will be used to examine the molecular-genetic nature of cellular commitment to segmental identity.
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