Dissecting the cellular and molecular mechanism underlying planar cell polarity s

描述（由申请人提供）：平面细胞极性（PCP）信号调节邻近细胞沿着平行于组织平面的轴的协调极化。它是许多细胞过程所必需的，包括耳蜗Corti器中毛细胞的均匀取向和动态会聚延伸（CE）过程。许多发育缺陷，包括耳聋、神经管闭合缺陷和肾缺陷，都与PCP信号传导中断有关。已知几种必需的PCP蛋白，如货车高格样2（Vangl 2）和卷曲蛋白（Fz），在耳蜗中以极化方式定位于细胞膜，其被认为介导相邻细胞之间感觉细胞极性的协调。然而，PCP信号领域的一个突出问题是动态CE过程如何也由PCP途径调节。这在很大程度上是由于缺乏了解的形态发生过程中的CE和PCP信号在这个过程中的分子作用。在本研究中，我们将以小鼠耳蜗为模型系统，结合联合收割机、小鼠遗传学、先进的成像技术以及分子和细胞生物学方法，着手解决PCP途径调控CE的关键问题。该提议的具体目的是1）表征CE期间的细胞极化过程，并评估耳蜗CE期间细胞形态极化变化中PCP信号传导的需求; 2）确定PCP蛋白Vangl 2在CE期间指导形态发生极化中的细胞作用。该提案的具体目标的完成将有助于建立一个完整的图片收敛延伸过程中的细胞极化，并确定是否需要驱动极化细胞插入在这个过程中的方向信息依赖于跨膜PCP蛋白的本地化。发起人（Chen）使用内耳作为模型系统探索PCP途径，在PCP领域取得了重大进展。该研究将为PCP途径影响的途径和疾病过程提供新的见解。

DESCRIPTION (provided by applicant): Planar cell polarity (PCP) signaling regulates coordinated polarization of neighboring cells along an axis parallel to the plane of the tissue. Itis required for a multitude of cellular processes, including uniform orientation of hair cells in the organ of Corti of the cochlea and the dynamic convergent extension (CE) process. A number of developmental defects including deafness, neural tube closure defects, and kidney defects are associated with disruption of PCP signaling. It is known that several essential PCP proteins, such as Van gogh-like 2 (Vangl2) and Frizzled (Fz), are localized to cellular membrane in a polarized manner in the cochlea, which is thought to mediate coordination of sensory cell polarity among neighboring cells. However, one outstanding question in the PCP signaling field is how the dynamic CE process is also regulated by the PCP pathway. This is largely due to the lack of understanding of the morphogenesis process of CE and the molecular roles of PCP signaling during the process. In this proposal, we will use the mouse cochlea as the model system and combine mouse genetics, advanced imaging, and molecular and cell biological approached to start addressing key issues in regulation of CE by the PCP pathway. The specific aims of this proposal are 1) to characterize the cellular polarization process during CE and assess the requirement for PCP signaling in polarized changes in cellular morphology during CE of the cochlea; 2) to determine the cellular role of the PCP protein, Vangl2, in directing morphogenetic polarization during CE. The completion of the specific aims of this proposal will aid in building a complete picture for cellular polarization during convergent extension and define whether the directional information needed to drive polarized cellular intercalation during this process is dependent upon localization of transmembrane PCP proteins. The sponsor (Chen) has made significant advances in the PCP field using the inner ear as a model system to explore the PCP pathway. The proposed study will provide novel insight into the pathway and disease processes influenced by the PCP pathway.