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.

项目总结 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构图。相邻像元之间的这种协调由平面控制 细胞极性(PCP)，从苍蝇到人类的一种保守的信号通路。优秀的范例和功能 PCP的读出，或集体极化，是哺乳动物皮肤上体毛的有序排列 沿着身体的前后轴线。PCP组分的遗传破坏导致严重的发育 疾病包括心肌病、纤毛病和神经管缺陷，如脊柱裂。我们缺少一个 详细了解以PCP通路为靶点如何导致发育障碍。重要的是 破坏小鼠的PCP会导致发育缺陷和胚胎死亡，也会导致 对胚胎表皮进行适当的纹饰，使小鼠皮肤成为研究胚胎表皮的合适模型系统。 五氯苯酚的保守生物学。PCP的一个显著特征是核心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黏附相互作用是如何组织不对称细胞连接的 协调组织的极性以及这种分子组装在人类疾病中是如何受到干扰的。有必要 了解Celsr1黏附是如何协调PCP不对称性的，最近发现 神经管和先天性心脏病患者中新的、可预测的致病基因Celsr1突变。 在此之前，我们的工作揭示了钙粘附素介导的二聚化或侧向聚集在组织中的作用 不对称的五氯苯酚络合物。我们假设Celsr1顺式二聚作用调控五氯酚的运输。 PCP建立过程中的复合体以及疾病相关Celsr1突变对Celsr1的不同损害 黏附和二聚化相互作用破坏发育过程中的PCP。利用哺乳动物的皮肤作为一种 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 基因方法，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的建立和维持。这些 研究将为调节五氯苯酚和那些在人类体内受到干扰的机制提供新的见解。 发育障碍。