Dissecting the cellular and molecular mechanism underlying planar cell polarity s

描述(申请人提供)：平面细胞极性(PCP)信号调节沿平行于组织平面的轴的相邻细胞的协调极化。它是许多细胞过程所必需的，包括耳蜗器Corti器官中毛细胞的统一定向和动态会聚延伸(CE)过程。包括耳聋、神经管闭合缺陷和肾缺陷在内的许多发育缺陷都与PCP信号的中断有关。众所周知，几种重要的PCP蛋白，如Van Gogh-like 2(Vangl2)和FrizzledFz(Fz)，以极化的方式定位在耳蜗细胞膜上，被认为是调节相邻细胞之间感觉细胞极性的协调。然而，PCP信号领域的一个悬而未决的问题是，动态CE过程如何也受到PCP途径的调控。这在很大程度上是由于对CE的形态发生过程以及PCP信号在该过程中的分子作用缺乏了解。在这个方案中，我们将以小鼠耳蜗为模型系统，结合小鼠遗传学、先进的成像技术以及分子和细胞生物学的方法，开始解决PCP途径调控CE的关键问题。这一建议的具体目的是：1)表征CE过程中的细胞极化过程，并评估PCP信号在CE过程中细胞形态极化变化中的需求；2)确定PCP蛋白Vangl2在CE过程中引导形态发生极化的细胞作用。这一提议的具体目标的完成将有助于构建收敛延伸过程中细胞极化的完整图景，并确定在这一过程中驱动极化细胞嵌入所需的方向信息是否依赖于跨膜PCP蛋白的定位。发起人(Chen)在PCP领域取得了重大进展，使用内耳作为模型系统来探索PCP途径。这项拟议的研究将为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.