Dynamics of vertebrate planar cell polarity proteins

 描述（由申请人提供）：平面细胞极性（PCP）信号传导系统是一种进化上保守的遗传模块，控制动物中的极化细胞行为，对脊椎动物发育至关重要。在PCP信号传导控制的许多行为中，运动纤毛的定向跳动是产生流体流动的中心，流体流动对于许多器官系统（包括气道）中的稳态和功能至关重要。尽管人类PCP基因突变与多种结构性出生缺陷有关，但PCP蛋白动力学的研究主要限于果蝇，而果蝇与哺乳动物不同，非常适合活体成像。该提案的直接目标是开发和利用新的工具，通过在脊椎动物纤毛上皮中的实时成像来探索PCP蛋白的动态。了解五氯苯酚的功能机制是发育生物学中的一项重要挑战，该提案将为社区提供易于采用的新工具。此外，拟议的实验将大大推进我们对脊椎动物特定的PCP信号机制的理解，为人类结构性出生缺陷，如神经管缺陷和先天性肢体畸形提供见解。

 DESCRIPTION (provided by applicant): The Planar Cell Polarity (PCP) signaling system is an evolutionarily conserved genetic module that controls polarized cell behavior in animals and is broadly essential for vertebrate development. Among the many behaviors controlled by PCP signaling is the oriented beating of motile cilia, which is central to generating the fluid flow tht is crucial for homeostasis and function in many organ systems, including the airway. Despite the fact that mutation of PCP genes in humans is associated with diverse structural birth defects, studies of PCP protein dynamics have been largely limited to Drosophila, which unlike mammals is highly amenable to live imaging. The immediate goal of this proposal is to develop and exploit novel tools for exploring the dynamics of PCP proteins via live imaging in a vertebrate ciliated epithelium. Understanding the mechanisms of PCP function is an important challenge in developmental biology, and this proposal will generate new, easily adopted tools for the community. Moreover, the proposed experiments will substantially advance our understanding of vertebrate-specific mechanisms of PCP signaling, providing insights into human structural birth defects such as neural tube defects and congenital limb anomalies.