Cellular and molecular regulation of upper lip fusion by p120-catenin

项目总结/摘要 颅骨和面部畸形是最常见的出生缺陷之一，这些缺陷往往会阻碍 受影响儿童的身心发展。在正常发育的儿童中，唇和初级腭 发育是一个多步骤的过程，包括鼻凹内陷，鼻突的生长， 内侧鼻突、外侧鼻突和上颌骨突的融合。这个过程的失败导致唇裂， 全世界每700个活产婴儿中就有一个发生，这使其成为最常见的颅面分娩 缺损然而，这一过程并不完全清楚，全面的细胞分析正常 唇发育仍然缺乏。 最近，连环蛋白δ 1（CTNND 1）突变与非综合征性唇裂相关， 眼睑唇齿综合征是一种主要特征为眼睑，牙齿， 尤其是上唇Ctnnd 1编码p120-catenin，一种最为人所知的维持粘附连接的蛋白质，但 以及其他较少研究的分子功能。细胞培养的研究表明，p120-连环蛋白也 功能调节肌动球蛋白收缩性和WNT信号传导的上游，所有这些作用在 组织形态发生我的初步数据显示，外胚层中Ctnnd 1的无效突变导致裂 嘴唇p120-catenin的每一个角色如何影响上唇发育仍然是未知的。本初步 数据支持p120-连环蛋白在唇发育期间颅面外胚层中的钙粘蛋白非依赖性作用。 在这里，我利用先进的成像和基因编辑的优势来研究细胞和分子 p120-catenin在上唇发育中的作用机制 拟议的工作将在加州大学杰弗里·布什博士的实验室进行 弗朗西斯科，它拥有一个专门的办公室，以培养博士后学者。实验室是 颅面生物学计划，一个活跃的社区，生产高素质的研究和提供 从教师到学员无与伦比的支持。这些因素将使我能够成功地执行 建议的工作，并获得独立研究的特殊培训。

Project Summary/Abstract Skull and facial abnormalities are among the most common birth defects, and such defects often hinder the physical and mental development of the affected child. In a normal developing child, lip and primary palate development is a multistep process that includes nasal pit invagination, outgrowth of nasal processes, and fusion of the medial nasal, lateral nasal, and maxillary processes. Failure of this process results in cleft lip, which occurs in around one in every 700 live births worldwide, making it the most common craniofacial birth defect. However, the process is not completely understood, and a comprehensive cellular analysis of normal lip development is still lacking. Recently, mutations in catenin delta 1 (CTNND1) have been correlated with non-syndromic cleft lip and blepharocheilodontic syndrome, a human condition mainly characterized by facial defects to the eyelids, teeth, and notably upper lip. Ctnnd1 encodes p120-catenin, a protein best known to maintain adherens junctions, but with other lesser studied molecular functions as well. Studies in cell culture have shown that p120-catenin also functions to regulate actomyosin contractility and upstream of WNT signaling, all roles that are important in tissue morphogenesis. My preliminary data shows that null mutations in Ctnnd1 in the ectoderm results in cleft lip. How each of the roles of p120-catenin influence upper lip development remains unknown. This preliminary data support a cadherin-independent role for p120-catenin in the craniofacial ectoderm during lip development. Here, I use strengths of advanced imaging and gene editing to investigate the cellular and molecular mechanisms p120-catenin functions in upper lip development. The proposed work will be performed in the laboratory of Dr. Jeffrey Bush at University of California San Francisco, which boasts a dedicated office to the training of postdoctoral scholars. The lab is a part of the Program in Craniofacial Biology, an active community producing high caliber research and offering unparalleled support from faculty to trainees. These factors will enable me to successfully carry out the proposed work and obtain exceptional training towards independent research.