Determining the role of cell-cell adhesions in palate closure - Project Summary This application is for Juliet S. King to pursue a Predoctoral Fellowship from the Ruth L. Kirschstein National Research Service Award (NRSA, F31). Ms. King is currently investigating tissue specific signaling modules in the oral epithelia during mammalian palatogenesis. This award will allow Ms. King to hone her cell and developmental biology skills and apply that expertise to her interests in craniofacial and oral biology. This proposal will advance our understanding of 1) periderm specific signaling programs and 2) the developmental function of heterotypic nectin interactions at the periderm-basal cell interface. Tissue specific and mechanistic insights into palatogenesis will provide clarity on cleft palate (CP) pathology and inform better genetic therapy strategies. With this opportunity, Ms. King will receive the training necessary for a career as an independent researcher with a focus on mentorship and education. Cleft palate (CP) is a common birth defect, affecting 1:1700 live births globally1. CP results from the failure to fuse the palatal shelves to separate the oral and nasal cavities2. Palate closure is a complex morphogenetic process that occurs during embryogenesis in both mice and humans. Like other morphogenetic processes, palate closure relies on cell-cell adhesions to generate proper tissue shape3. NECTIN1 and ECAD are two types of cell-cell contact receptors that when mutated have been causally associated with CP in humans4–7. Recent work from our lab has shown that loss of AFDN, the NECTIN1 downstream partner, in the oral epithelia drives CP. Importantly, the oral epithelium is made up of two compartments: the basal keratinocytes and periderm. Until recently, these two compartments have been experimentally treated as one, obscuring the tissue specific roles of either in palatogenesis. Thus, the goal of my project is to elucidate the requirement of periderm-specific signaling and the role of receptor signaling at the periderm-basal cell interface. I plan to test the hypothesized model that NECTIN1 in the basal layer interacts with NECTIN4 in the periderm to mesenchymal fusion and periderm-basal cell attachment in palate closure. To do this, I will 1) perform periderm-specific gene deletion studies and determine its effect on MES dissolution during palate fusion. In addition, I will 2) disrupt the NECTIN1-NECTIN4 heterotypic boundary between periderm and basal cells to define the role of heterotypic NECTIN interactions in palatogenesis. Our experiments take advantage of specialized cell biological and microscopy skills to address knowledge gaps in oral biology.
