We know very little about the mechanisms of morphogenesis and differentiation during post-embryonic stages of development in vertebrates. Nevertheless, an understanding of the factors controlling these later events is absolutely essential for a fuller understanding of the form taken by adult traits, and how genetic and environmental perturbations yield morphological defects and disease syndromes. One model for understanding mammalian fetal and perinatal development is the metamorphosis of fishes and amphibians, which include body shape, skin structure and pigmentation, homeostatic activities, and appendage morphology. The studies proposed here will take an explicitly genetic approach to understanding metamorphosis, and by extension, post-embryonic development in mammals. These analyses will use the genetically tractable model vertebrate, the zebrafish, Danio rerio. First, a genetic screen will be undertaken to isolate new mutations in genes required for generalized metamorphosis of body shape as well as metamorphosis of the pigment pattern, and a subset of the resulting mutants will be molecularly cloned. To identify genes required both during early embryogenesis and metamorphic periods, this screen will seek to identify conditional alleles that express mutant phenotypes only at a restrictive rearing temperature (thus early embryonic lethality can be circumvented by rearing individuals, initially. at a permissive temperature). Second, a targeted mutant screen will be conducted to isolate mutations in candidates genes suspected to have roles in metamorphosis from studies of amphibians and mammals. This approach will employ both the generation of chromosomal deletions harboring these candidates, and subsequently, the induction of point mutations in these genes. Third, newly isolated mutants will be characterized by assessing critical periods for gene function (via temperature shift experiments), and by determining how and where these genes are required relative to previously identified genes and genetic pathways (via analysis of molecular marker expression in wildtype and mutant individuals). Together these analyses will provide novel insights into the controls of postembryonic development, and will generate a host of resources that will be of value to other biomedical researchers studying zebrafish developmental genetics and human disease.
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