Cellular mechanisms of palatal shelf outgrowth

Project Summary/Abstract Craniofacial morphogenesis involves a multitude of cell behaviors, including mesenchymal cell movements that change the physical properties of tissues, culminating in changes in tissue shape. During secondary palate morphogenesis the palatal shelves undergo a dramatic transformation in tissue shape that includes outgrowth,

extension, elevation, adhesion, and fusion to form a continuous structure. Cleft palate, occurring in 1:1500 live births, can result from the failure of any step in this process, however, our understanding of the mesenchymal cell behaviors that regulate tissue shape changes during secondary palate development is limited. My lab’s

previous research Indicates that Efnb1 is a key regulator of mesenchymal cell position and embryonic boundary formation in multiple contexts, but how these changes cause a cleft palate phenotype is not clear. Our preliminary data indicate that loss of function of the Shrm4 gene genetically interacts with Efnb1 loss, resulting in more

severe craniofacial dysmorphology and a dramatically increased incidence of cleft palate. This proposal aims to establish the interplay between Efnb1 and Shrm4, and their impacts on the dynamic cell behaviors involved in secondary palate tissue shape change. My proposal takes advantage of mouse genetics expertise in my sponsor

lab and three-dimensional imaging and quantitative analysis approaches that I have developed to understand mesenchymal cell behaviors, as they relate to secondary palate shape change normally and upon loss of Efnb1. I will test the hypothesis that EPHRIN-B1 and SHROOM4 regulate the actomyosin cytoskeleton to control palatal

shelf shape change. Through these studies, I aim to improve understanding of the regulation of palatal outgrowth, mesenchymal organization, and tissue shape during normal and cleft palate morphogenesis. This is highly relevant to the etiology of CFNS, which is caused by mutations in the EFNB1 gene, and which includes cleft

palate in its spectrum.