Project Summary/Abstract Craniofacial abnormalities are among the most common birth defects, affecting more than one in every seven hundred live births worldwide. Recent studies found that mutations in CTNND1 are amongst the most common monogenic causes of cleft lip. Ctnnd1 encodes p120-catenin (p120ctn), a protein best known to maintain adherens junctions, but which has multiple molecular functions that are important in tissue morphogenesis. A powerful gene-editing approach in mice was used to create Ctnnd1 mutant alleles that individually disrupt distinct p120ctn protein functions, providing preliminary data that revealed the importance of p120ctn-cadherin interactions and the dispensability of E-cadherin in lip development, presenting a paradox. This proposal leverages newly developed mouse alleles and novel live imaging approaches to elucidate molecular mechanisms underlying cleft lip in Ctnnd1 mutants. These approaches reveal striking actomyosin dynamics during lip fusion and suggest a model in which p120ctn functions to fulfil a spatiotemporally specific demand to withstand high actomyosin-generated forces and transduce mechanical signals. New mouse alleles, live imaging approaches, and force manipulations will be leveraged to understand how p120ctn regulates the cellular behaviors and cellular-generated forces that drive lip fusion. The project and training plan outlined in this proposal will lay the groundwork for Dr. Teng’s independent research program at the intersection of craniofacial biology and cell biology. During this mentored period, she will train in new techniques with major focus on quantitative image analysis, work closely with her advisory team, and enroll in complementary coursework to acquire the necessary expertise to accomplish her research and career goals. She will also undertake a program of training to support her professional development as a mentor and supervisor. In addition to the experienced community of craniofacial biologists, UCSF also boasts a dedicated program for the training of postdoctoral scholars. The training described in this proposal will equip Dr. Teng with the necessary skill set and robust research platform to launch her independent research career.