Cadherin regulation of planar polarity

钙粘蛋白对平面极性的调节

基本信息

批准号：
10711228
负责人：
Sara N Stahley
金额：
$ 41.19万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-06-30
项目状态：
未结题

项目摘要

PROJECT SUMMARY During human development, cells interact with one another to drive collective and oriented cell behaviors that control organ formation and tissue patterning. This coordination between neighboring cells is governed by planar cell polarity (PCP), a signaling pathway conserved from flies to humans. An excellent example and functional read-out of PCP, or collective polarization, is the ordered alignment of body hairs across the mammalian skin along the anterior-posterior body axis. Genetic disruption of PCP components leads to severe developmental disorders including cardiomyopathies, ciliopathies, and neural tube defects such as spina bifida. We lack a detailed understanding for how targeting of the PCP pathway leads to developmental disorders. Importantly, PCP disruption in mice that results in developmental defects and embryonic lethality also results in a failure to properly pattern the embryonic epidermis, thus making the moue skin a suitable model system to study the conserved biology of PCP. A hallmark feature of PCP is the asymmetric localization of core PCP proteins at cell borders within a junctional complex organized via intercellular interactions of cadherin family member Celsr1. Our long-term goal is to understand how Celsr1 adhesive interactions organize asymmetric cell junctions to coordinate tissue polarity and how this molecular assembly is perturbed in human disease. The need to understand how Celsr1 adhesion coordinates PCP asymmetry is underscored by the recent identification of novel, predicted pathogenic, Celsr1 mutations in patients with neural tube and congenital heart defects. Previously, our work revealed a role for cadherin-mediated dimerization, or lateral clustering, in the organization of asymmetric PCP complexes. We hypothesize that Celsr1 cis-dimerization regulates trafficking of PCP complexes during PCP establishment and that disease-associated Celsr1 mutations differentially impair Celsr1 adhesion and dimerization interactions to disrupt PCP during development. Using the mammalian skin as a conduit for PCP function, along with molecular biology, protein biochemistry, advanced imaging and in vivo genetic approaches, our research program will uncover the pathomechanisms of human disease-associated Celsr1 mutations and reveal how Clesr1 dimerization regulates PCP establishment and maintenance. These studies will provide novel insight into the mechanisms that regulate PCP and those that are perturbed in human developmental disorders.

项目概要在人类发育过程中，细胞相互作用，驱动集体和定向的细胞行为，控制器官形成和组织模式。相邻单元之间的这种协调由平面控制细胞极性（PCP），从果蝇到人类保守的信号通路。一个很好的例子和功能 PCP 或集体极化的读数是哺乳动物皮肤上体毛的有序排列沿着身体前后轴。 PCP 成分的基因破坏导致严重的发育障碍疾病包括心肌病、纤毛病和脊柱裂等神经管缺陷。我们缺少一个详细了解 PCP 途径的靶向如何导致发育障碍。重要的是，小鼠 PCP 破坏会导致发育缺陷和胚胎致死，也会导致无法正确地构建胚胎表皮的图案，从而使小鼠皮肤成为研究胚胎表皮的合适模型系统 PCP 的保守生物学。 PCP 的一个标志性特征是核心 PCP 蛋白在细胞中的不对称定位通过钙粘蛋白家族成员 Celsr1 的细胞间相互作用组织的连接复合体内的边界。我们的长期目标是了解 Celsr1 粘附相互作用如何组织不对称细胞连接协调组织极性以及这种分子组装在人类疾病中如何受到干扰。需要了解 Celsr1 粘附协调 PCP 不对称性如何通过最近的鉴定得到强调神经管和先天性心脏缺陷患者中新的、预测的致病性 Celsr1 突变。此前，我们的工作揭示了钙粘蛋白介导的二聚化或横向聚类在组织中的作用不对称PCP复合物。我们假设 Celsr1 顺式二聚化调节 PCP 的运输 PCP 建立过程中的复合物以及疾病相关的 Celsr1 突变会不同程度地损害 Celsr1 粘附和二聚化相互作用会在发育过程中破坏 PCP。使用哺乳动物的皮肤作为 PCP 功能的管道，以及分子生物学、蛋白质生物化学、先进成像和体内遗传方法，我们的研究计划将揭示人类疾病相关的病理机制 Celsr1 突变并揭示 Clesr1 二聚化如何调节 PCP 建立和维持。这些研究将为调节 PCP 和影响人类的机制提供新的见解发育障碍。