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

项目摘要/摘要 头骨和面部畸形是最常见的出生缺陷之一，这种缺陷通常会阻碍 受影响儿童的身体和精神发育。在正常发育的儿童中，嘴唇和主腭部 发育是一个多步骤的过程，包括鼻小窝内陷、鼻突突起和 内侧鼻突、外侧鼻突和上颌突的融合。这个过程的失败会导致唇裂， 全世界每700名活产儿中就有一名发生这种情况，使其成为最常见的头面部出生 叛逃。然而，这一过程并不完全清楚，而对正常细胞的全面分析 唇部发育仍然不足。 最近，连环蛋白增量1(CTNND1)的突变与非综合征性唇裂和 眼睑唇齿综合征，是一种人类疾病，主要表现为眼睑、牙齿和皮肤的面部缺陷， 值得注意的是上嘴唇。Ctnnd1编码p120-连环蛋白，这是一种众所周知的维持粘连连接的蛋白质，但 以及其他较少研究的分子功能。细胞培养研究表明，p120-连环蛋白也 调节肌动蛋白收缩的功能和WNT信号的上游，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Ctnnd1的零突变会导致裂隙 利普。P120-catenin的每一种作用如何影响上唇发育尚不清楚。这是初步的 数据支持p120-catenin在嘴唇发育过程中在头面部外胚层中起不依赖钙粘附素的作用。 在这里，我使用先进的成像和基因编辑的优势来研究细胞和分子 P120-连环蛋白在上唇发育中的作用机制。 这项拟议的工作将在加州大学杰弗里·布什博士的实验室进行 旧金山拥有一个专门培训博士后学者的办公室。该实验室是 颅面生物学计划，一个活跃的社区，产生高水平的研究和提供 教职员工对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，并获得针对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.