Cadherin regulation of planar polarity

钙粘蛋白对平面极性的调节

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10711228
• 关键词: Adhesions; Adhesives; Anterior; Behavior Control; Biological; Biological Models; Biology; Cadherins; Cardiomyopathies; Cell Communication; Cells; Complex; Congenital Heart Defects; Defect; Development; Dimerization; Disease; Embryo; Epidermis; Failure; Family member; Genetic; Goals; Hair; Human; Human Development; Image; Impairment; Intercellular Junctions; Labyrinth; Lateral; Maintenance; Mediating; Molecular Biology; Mus; Mutation; Neural Tube Defects; Neural tube; Organ; Pathogenicity; Pathway interactions; Patients; Pattern; Protein Biochemistry; Proteins; Regulation; Research; Role; Signal Pathway; Skin; Spinal Dysraphism; Tissues; Work; cell behavior; ciliopathy; developmental disease; fly; genetic approach; human disease; in vivo; insight; molecular assembly/self assembly; novel; planar cell polarity; programs; trafficking

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.

项目摘要 在人类发展过程中，细胞相互相互作用，以驱动集体和定向细胞行为 控制器官形成和组织模式。相邻细胞之间的这种协调受平面的控制 细胞极性（PCP），一种从苍蝇到人保守的信号通路。一个很好的例子和功能 读出PCP或集体两极化是在哺乳动物皮肤上的身体头发的有序对齐 沿前后轴轴。 PCP组件的遗传破坏会导致严重发展 疾病，包括心肌病，纤毛病和神经管缺陷，例如脊柱裂。我们缺乏 详细了解靶向PCP途径如何导致发育障碍。重要的是， 导致发育缺陷和胚胎致死性的小鼠的PCP破坏也导致未能 正确对胚胎表皮进行了正确的模型，从而使Moue皮肤成为研究的合适模型系统 PCP的保守生物学。 PCP的标志性特征是核心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络合物内的边界。 我们的长期目标是了解CELSR1粘合剂相互作用如何组织不对称的细胞连接到 协调组织极性以及该分子组装如何在人类疾病中干扰。需要 了解CELSR1粘附如何坐标PCP不对称是通过最近鉴定的 神经管和先天性心脏缺陷患者的新型，预测的致病性，CELSR1突变。 以前，我们的工作在组织中揭示了钙粘蛋白介导的二聚体或横向聚类的作用 不对称PCP复合物。我们假设CELSR1顺式 - 二聚体调节PCP的贩运 PCP建立期间的复合物以及与疾病相关的CELSR1突变差异损害CELSR1 在开发过程中破坏PCP的粘附和二聚化相互作用。将哺乳动物皮作为 PCP功能的导管，以及分子生物学，蛋白质生物化学，高级成像和体内 遗传方法，我们的研究计划将发现与人类疾病相关的病理机理 CELSR1突变并揭示CLESR1二聚化如何调节PCP的建立和维护。这些 研究将为调节PCP的机制和人类扰动的机制提供新的见解 发育障碍。