Investigating mechanisms of tissue polarity during development and disease

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PROJECT SUMMARY Organ formation and tissue patterning during human development rely on collective and oriented cell behaviors. Planar cell polarity (PCP), a signaling pathway conserved from flies to humans, governs this coordination between neighboring cells. PCP is well represented by the ordered alignment of body hairs across the mammalian skin along the anterior-posterior body axis. Deficiencies in PCP protein function result in severe developmental defects including cardiomyopathies, ciliopathies and neural tube defects such as spina bifida. How PCP pathway disruption results in developmental disorders remains poorly understood. Importantly, PCP disruption resulting in developmental defects and embryonic lethality in mice also results in a failure to properly pattern the embryonic epidermis, thus the mouse skin is a suitable model system with and hair follicle polarity being a tractable read-out of PCP function. A defining feature of PCP is the asymmetric localization of core PCP proteins Frizzled 6 (Fz6) and Van Gogh like protein 2 (Vangl2) at cell-cell borders. Intercellular interactions of atypical cadherin Celsr1 is required for the Fz6 and Vangl2 localization at cell borders. Yet, we do not understand how Celsr1 adhesion organizes asymmetric PCP junctions or how this is regulated during development. The need to understand how Celsr1 functions as a driver of Fz6-Vangl2 asymmetry at junctions is underscored by the recent identification of novel, predicted pathogenic, Celsr1 mutations in patients with neural tube and congenital heart defects. The overall goal of this proposal is to better understand how these disease-associated Celsr1 mutations, particularly those that map to the Celsr1 domains responsible for cell adhesion, contribute to human developmental disorders. Using the murine epidermis as model system for PCP function, along with cell and molecular biology, biochemical, advanced optical imaging and in vivo genetic approaches, I will test the hypothesis that disease-associated Celsr1 mutations perturb Celsr1 cell adhesion and alter the establishment of PCP asymmetry during development. This hypothesis will be interrogated in the following specific aims: 1) Determine how disease-associated Celsr1 mutations impact Celsr1 adhesion and signaling, and 2) Determine how disease-associated Celsr1 mutations impact PCP establishment. The proposed aims will reveal pathomechanisms of developmental disorders that target Celsr1 function while also providing key insight into how Celsr1 regulates PCP establishment. Fellowship support to complete the proposed research and crafted training plan, along with guidance from my mentoring team and the environment at the Penn State College of Medicine, will be instrumental in my career development toward my goal of leading an independent and diverse research team.