In order to generate the craniofacial skeleton, neural crest progenitors need to adopt one specific fate verses another. It is the long-term goal of my laboratory to determine the molecular mechanisms that regulate cell fate determination of neural crest cell and their derivatives. Neural crest cells arise from the lateral portion of the neural plate and migrate extensively to form the craniofacial skeleton as well as other derivatives. The specific objective of this application is to determine the genetic requirement for prdm1 in the branchial arches of zebrafish and mouse, to determine the genetic interactions of prdm1 in the branchial arch, and to determine whether prdm1 actively regulates cell proliferation and/or differentiation in neural crest derived mesenchyme in the branchial arches of zebrafish and mouse. Our hypothesis is that prdm1 is crucial for formation of neural crest cell differentiation. A series of experiments to test this hypothesis is proposed. We propose to test the hypothesis that prdm1 required within the branchial arch for differentiation of the neural crest derived mesenchyme into ceratobranchial skeleton. In addition, we will determine the genetic hierarchy around prdm1 to test the hypothesis that prdm1 acts downstream of key craniofacial regulators and at the same level as hand2. Lastly, we will test the hypothesis that prdm1 acts to promote cell differentiation by promoting the proliferation of precursor cells, without affecting cell fate and is required within the neural crest derived mesenchyme in both zebrafish and mouse. Towards these goals, we will take advantage of the zebrafish and the mouse systems, because of their well-established experimental and genetic methods make a detailed analysis of this process feasible. As an outcome of these studies, it is expected to determine that the prdm1 transcription factor plays critical role in the differentiation of neural crest cells. This will be important in determining the genetic pathways that are important for neural crest development, which in turn will be an important step in preventative measures in human congenital defects, such as cleft lip and palate. ? ? ?
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