One of the main goals of developmental biology is to elucidate the molecular mechanisms that govern the generation of distinct cell types from unspecified precursors. A detailed knowledge of these mechanisms will not only help us understand fundamental principles of normal ontogeny but also explain, and ultimately correct, instances where development has derailed and disease has resulted. The goal of our studies is to characterize the network of factors involved in the generation of pigment cells which are of crucial importance for the development and function of mammalian sensory organs. Currently we are analyzing how specific signal transduction pathways coordinate gene expression, and hence lineage decisions, in neural crest and neuroepithelial pigment cell precursors. We have chosen to focus on the MAPkinase pathway and the regulation of the microphthalmia-associated transcription factor Mitf, which are both critical for the development of the neuroepithelial-derived pigment cells in the eye and the neural crest-derived pigment cells in the inner ear and coat. A thorough understanding of how these factors affect pigment cell development requires the use of genetic models. Among them, we have chosen to use the laboratory mouse as experimental system for it offers easy manipulation of its genome, relevance to human disease, and pre- existing, large allelic series of mutations in both Mitf and receptor tyrosine kinase pathways. In a multipronged approach that employs both in vivo and in vitro methods, we are establishing genetic hierarchies between the different factors, are studyingthe fate of precursor cells in mutant embryos, and are determining the relative importance of transcriptional and posttranscriptional regulation of gene function. Ultimately, the interaction of these factors leads to activation of a set of target genes which in turn define the descendent cell type. To identify such target genes, we are analyzing mutant and wild type embryos using advanced microdissection and molecular techniques. - neural crest, central nervous system patterning, eye, sensorineural deafness, Waardenburg syndrome, MITF, bHLH-Zip, transgenic mice
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