Signaling control and cellular basis of craniofacial morphogenesis and congenital disease

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Project Summary Congenital craniofacial anomalies are common and arise from cellular changes that cause aberrant tissue-level alterations in shape. Though significant understanding of the gene regulatory networks that pattern craniofacial development has been achieved, knowledge regarding the cellular and physical processes driving craniofacial morphogenesis lags behind. A particular paucity of information exists on the cellular changes that drive specific craniofacial dysmorphologies. In recent years, my laboratory has assembled a battery of tools and established a network of collaborations to address the signaling control of physical aspects of morphogenesis. By generating new live imaging platforms for the study of lip and secondary palate fusion, we have identified novel cellular behaviors that contribute to this process. We have pursued a detailed understanding of the cellular mechanisms of craniofrontonasal syndrome, a condition that we have learned results from aberrant cell segregation behavior and resultant changes in tissue shape. We have established the first hiPSC model of a craniofacial condition, allowing us to address questions of cellular morphogenesis in a human system for the first time. Here we propose a series of new directions that focus on the cellular basis of craniofacial morphogenesis and how it goes wrong in congenital craniofacial conditions. These include three main goals: 1) Understand the control of mesenchymal cell movement in shaping craniofacial tissues 2) Elucidate mechanisms of craniofacial epithelial tissue fusion at cellular and molecular resolution 3) Elaborate novel regulators of mammalian craniofacial morphogenesis by use of cutting edge CRISPR/Cas9 methodology in a human craniofacial disease-biased mutagenesis approach. Achieving these goals will drive understanding of basic principles of cellular morphogenesis in craniofacial development and increasingly provide opportunities to adapt these principles toward therapeutic and tissue engineering approaches to treat congenital craniofacial anomalies.