Golgb1 in Craniofacial Development

描述（由申请人提供）：腭裂是一种常见的重大出生缺陷，需要在出生后不久进行手术干预，并对受影响的个体具有重大的长期健康影响。虽然在过去的二十年中，对腭裂发育的分子调控的理解取得了巨大的进展，但目前已知的遗传原因占人类腭裂病理学的不到20%。通过表型驱动的诱变筛选和全外显子组测序分析，我们已经确定了一个新的腭裂突变小鼠品系的Golgb1基因的功能缺失突变。Golgb1编码定位于高尔基体的大型跨膜蛋白。尽管一些人类发育障碍与高尔基体相关蛋白的突变有关，但很少有研究表征高尔基体和高尔基体相关蛋白在发育和器官发生中的作用。在这个项目中，我们将产生携带Golgb 1独立基因靶向突变的小鼠，以证实Golgb 1功能丧失导致腭裂。我们将确定特定的细胞，分子和形态发生过程中腭发育依赖于Golgb1功能。这些研究将为腭发育的分子和细胞机制以及颅面出生缺陷的致病机制提供新的见解。

DESCRIPTION (provided by applicant): Cleft palate is a common major birth defect that requires surgical intervention shortly after birth and has significant long-term health implication 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.