Wnt/Frizzled-PCP signaling in development and disease

发育和疾病中的 Wnt/Frizzled-PCP 信号传导

• 批准号: 10631665
• 负责人: Marek Mlodzik
• 金额: $ 66.63万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631665
• 关键词: Address; Adult; Affect; Apical; Biological; Cell Adhesion; Cell Polarity; Cell division; Cells; Cellular biology; Chest; Cilia; Complex; Cytoplasm; Cytoskeleton; Defect; Development; Disease; Dissection; Drosophila genus; Epithelial Cells; Epithelium; Fatty acid glycerol esters; Genetic Screening; Homeostasis; Infertility; Kinesin; Labyrinth; Ligands; Link; Maintenance; Malignant Neoplasms; Mammals; Mediating; Medical; Membrane; Microtubules; Molecular; Neural Tube Closure; Nuclear Translocation; Organ; Organogenesis; Pathway interactions; Pattern; Physiological; Process; Proteins; Proto-Oncogenes; Regulation; Research; Respiratory System; Role; Signal Transduction; Skin; Specificity; Structure; Tissues; Tumor Suppressor Proteins; WNT Signaling Pathway; Wing; beta catenin; ciliopathy; convergent extension; deafness; experimental study; fluidity; gastrulation; human disease; insight; member; planar cell polarity; polarized cell; receptor; response; stem cells

Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis within the epithelial plane, called Planar Cell Polarity (PCP). Cell polarity and associated ordered cellular arrangements and patterning during organogenesis and homeostasis depend on Wnt-signaling mediated PCP mechanisms. Classical examples of PCP organized tissues include in Drosophila adult cuticular structures, like the wing and thorax epithelia, and in mammals striking aspects of PCP are evident in the skin, the inner ear epithelium, or the respiratory system and most other internal organs. Moreover, convergent extension processes during gastrulation and neural tube closure require Wnt/PCP signaling. Similarly, the PCP pathway is linked to the regulation of asymmetric cell divisions in stem cells of many organs. Studies of PCP establishment in Drosophila continue to serve as a paradigm to unravel this type of polarity in development and human disease. PCP is coordinated by Wnt ligand signals, resulting in asymmetric localization of their receptors, the Frizzled (Fz) proteins, and associated signaling cascade. Core Wnt-Fz/PCP factors are required to interpret polarity within the cell and relay this to neighboring cells. All core PCP members are evolutionarily conserved and regulate all PCP aspects studied. This Wnt-pathway is distinct from canonical Wnt-Fz/β-catenin signaling (and correct regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical for development and disease). The cellular mechanism(s) affecting polarity downstream of either Fz or Vang (Vangl1/2 in mammals), with Vang/Vangl being the intercellular transmembrane PCP- partners of Fz proteins, remain poorly understood. The focus of my lab’s research, and this application, is to (i) continue to investigate the mechanistic interactions of the core PCP signaling factors and the resulting cellular read-outs and intracellular responses, (ii) to establish connections between the core Fz/PCP pathway and the Fat/Ds-PCP cassette, and (iii) – a recent addition to our efforts - to dissect the non-ciliary function(s) of ciliary proteins in both, canonical Wnt/β-catenin signaling and Wnt/PCP pathways, with the advantage of being able to do so in non-ciliated Drosophila cells. This recent focus originates from genetic screens, identifying such non-ciliary functions of cilia associated factors. Exciting ongoing experiments are addressing the physiological significance of regulatory interactions between the Fz- and Vang-complexes, and how these affect either Fz or Vang cytoplasmic effectors and their cell biological responses to PCP signaling, including effects on cell adhesion and tissue fluidity, or its impact on cytoskeletal regulation. Another major focus is based on our identification of the Kinesin-2/IFT-A complex being required for the nuclear translocation of β-catenin. We are continuing our mechanistic dissection of this exciting and unexpected microtubule associated process. Information acquired here will advance our fundamental understanding of cellular polarization and the role of ciliary proteins in either Wnt-signaling pathway, and also provide insight into Wnt-signaling disease contexts.

上皮细胞因其功能而在两个轴上极化，即普遍存在的顶端-基底极性和第二个轴 上皮平面内，称为平面细胞极性（PCP）。细胞极性和相关的有序细胞 器官发生和稳态过程中的排列和模式取决于 Wnt 信号传导介导的 PCP 机制。 PCP 组织组织的经典例子包括果蝇成体角质层结构，例如 翅膀和胸部上皮细胞，在哺乳动物中，五氯苯酚的显着特征在皮肤、内耳中很明显 上皮，或呼吸系统和大多数其他内脏器官。此外，收敛扩展 原肠胚形成和神经管闭合过程需要 Wnt/PCP 信号传导。同样，PCP 途径 与许多器官干细胞不对称细胞分裂的调节有关。五氯苯酚研究 果蝇中的建立继续作为揭示这种发展和极性的范例 人类疾病。 PCP 由 Wnt 配体信号协调，导致其定位不对称 受体、卷曲 (Fz) 蛋白和相关的信号级联。需要核心 Wnt-Fz/PCP 因子 解释细胞内的极性并将其传递给邻近的细胞。所有核心 PCP 成员均已进化 保护和规范研究的所有五氯苯酚方面。该 Wnt 通路与典型的 Wnt-Fz/β-catenin 不同 信号传导（以及两条 Wnt 通路之间信号传导特异性的正确调节，由相同的信号激活） 受体，对于发育和疾病至关重要）。影响下游极性的细胞机制 Fz 或 Vang（哺乳动物中的 Vangl1/2），其中 Vang/Vangl 是细胞间跨膜 PCP- Fz 蛋白的伴侣仍然知之甚少。我实验室的研究和本应用的重点是 (i) 继续研究核心 PCP 信号传导因子的机制相互作用以及由此产生的细胞 读出和细胞内反应，(ii) 建立核心 Fz/PCP 途径和 Fat/Ds-PCP 盒，以及 (iii)——我们最近的努力——剖析睫状体的非睫状功能 经典 Wnt/β-连环蛋白信号传导和 Wnt/PCP 通路中的蛋白质，其优点是能够 在非纤毛果蝇细胞中这样做。最近的焦点源于基因筛选，识别出这样的 非纤毛功能的纤毛相关因素。正在进行的令人兴奋的实验正在解决生理学问题 Fz 和 Vang 复合物之间调节相互作用的重要性，以及它们如何影响 Fz 或 Vang 细胞质效应器及其对 PCP 信号传导的细胞生物学反应，包括对细胞的影响 粘附和组织流动性，或其对细胞骨架调节的影响。另一个主要焦点是基于我们 鉴定 β-连环蛋白核易位所需的驱动蛋白-2/IFT-A 复合物。我们是 继续我们对这个令人兴奋和意想不到的微管相关过程的机械解剖。 这里获得的信息将增进我们对细胞极化和细胞极化作用的基本理解 Wnt 信号通路中的纤毛蛋白，并且还提供对 Wnt 信号疾病背景的深入了解。