Cleft palate is a common major birth defect that requires surgical intervention shortly after birth and has significant long-term health implications for the affected individuals. Although there has been tremendous progress in the understanding of molecular regulation of palate development in the last twenty years, currently known genetic causes account for less than 20% of cleft palate pathology in humans. Through a phenotype-driven mutagenesis screen and whole exome sequencing analyses, we have identified a loss-of-function mutation in the Golgb1 gene in a new cleft palate mutant mouse strain. Golgb1 encodes a large transmembrane protein localized to the Golgi apparatus. Although several human developmental disorders have been associated with mutations in Golgi-associated proteins, few studies have characterized the roles of Golgi and Golgi-associated proteins in development and organogenesis. In this project, we will generate mice carrying an independent gene-targeted mutation in Golgb1 to confirm that loss of function of Golgb1 causes cleft palate. We will identify specific cellular, molecular, and morphogenetic processes during palate development that depend on Golgb1 function. These studies will provide novel insights into the molecular and cellular mechanisms of palate development and pathogenic mechanisms of craniofacial birth defects.
Cleft palate is a common birth defect, occurring in about 1 in 1000 live births worldwide. This research project investigates the causes of cleft palate, which will provide new knowledge to improve family counseling and ultimately lead to development of strategies for prevention of such birth defects.