Cellular and molecular regulation of upper lip fusion by p120-catenin

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Project Summary/Abstract Skull and facial abnormalities are among the most common birth defects, and such defects often hinder the physical and mental development of the affected child. In a normal developing child, lip and primary palate development is a multistep process that includes nasal pit invagination, outgrowth of nasal processes, and fusion of the medial nasal, lateral nasal, and maxillary processes. Failure of this process results in cleft lip, which occurs in around one in every 700 live births worldwide, making it the most common craniofacial birth defect. However, the process is not completely understood, and a comprehensive cellular analysis of normal lip development is still lacking. Recently, mutations in catenin delta 1 (CTNND1) have been correlated with non-syndromic cleft lip and blepharocheilodontic syndrome, a human condition mainly characterized by facial defects to the eyelids, teeth, and notably upper lip. Ctnnd1 encodes p120-catenin, a protein best known to maintain adherens junctions, but with other lesser studied molecular functions as well. Studies in cell culture have shown that p120-catenin also functions to regulate actomyosin contractility and upstream of WNT signaling, all roles that are important in tissue morphogenesis. My preliminary data shows that null mutations in Ctnnd1 in the ectoderm results in cleft lip. How each of the roles of p120-catenin influence upper lip development remains unknown. This preliminary data support a cadherin-independent role for p120-catenin in the craniofacial ectoderm during lip development. Here, I use strengths of advanced imaging and gene editing to investigate the cellular and molecular mechanisms p120-catenin functions in upper lip development. The proposed work will be performed in the laboratory of Dr. Jeffrey Bush at University of California San Francisco, which boasts a dedicated office to the training of postdoctoral scholars. The lab is a part of the Program in Craniofacial Biology, an active community producing high caliber research and offering unparalleled support from faculty to trainees. These factors will enable me to successfully carry out the proposed work and obtain exceptional training towards independent research.