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 在人类发育过程中，细胞相互作用以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 细胞极性（PCP），从苍蝇到人类保守的信号通路。一个很好的例子和功能 PCP或集体极化的读出是哺乳动物皮肤上体毛的有序排列 沿着前后体轴。五氯苯酚成分的遗传破坏导致严重的发育障碍， 疾病包括心肌病、纤毛病和神经管缺陷如脊柱裂。我们缺乏一个 详细了解五氯苯酚通路的靶向作用如何导致发育障碍。重要的是， 五氯苯酚在小鼠体内的破坏会导致发育缺陷和胚胎死亡，也会导致 适当的模式胚胎表皮，从而使小鼠皮肤一个合适的模型系统，研究 五氯苯酚的保守生物学PCP的一个标志性特征是核心PCP蛋白在细胞内的不对称定位， 边界内的连接复合体组织通过细胞间的相互作用的钙粘蛋白家族成员Celsr1。 我们的长期目标是了解Celsr1粘附相互作用如何组织不对称的细胞连接， 协调组织极性以及这种分子组装如何在人类疾病中受到干扰。需要 了解Celsr1粘附如何协调PCP不对称性是通过最近的鉴定来强调的， 神经管和先天性心脏病患者中新的预测致病性Celsr1突变 以前，我们的工作揭示了钙粘蛋白介导的二聚化，或横向集群，在组织中的作用， 不对称PCP复合物的合成我们假设Celsr1顺式二聚体调节PCP的运输 复合物在PCP建立和疾病相关的Celsr1突变差异损害Celsr1 粘附和二聚化相互作用，以在发育过程中破坏五氯苯酚。利用哺乳动物的皮肤 PCP功能的管道，沿着分子生物学，蛋白质生物化学，先进的成像和体内 遗传学方法，我们的研究计划将揭示人类疾病相关的病理机制， Celsr1突变，揭示了Clesr1二聚化如何调节PCP的建立和维持。这些 这些研究将为五氯苯酚的调节机制和人类中受到干扰的机制提供新的见解。 发育障碍