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.

上皮细胞在两个轴上极化其功能，无处不在的顶碱极性和第二轴 在上皮平面中，称为平面细胞极性（PCP）。细胞极性和相关的有序细胞 在器官发生和稳态期间的布置和图案取决于信号介导的PCP 机制。 PCP有组织组织的经典例子包括果蝇成人可爱的结构，例如 翅膀和胸皮上皮，以及在哺乳动物中引人注目的PCP方面是皮肤中的证据 上皮或呼吸系统和大多数其他内部器官。此外，收敛扩展 口水和神经管闭合过程中的过程需要WNT/PCP信号传导。同样，PCP途径 与许多器官干细胞中不对称细胞分裂的调节有关。 PCP研究 在果蝇中建立的建立继续是揭露这种发展中这种极性和的范式 人类疾病。 PCP由Wnt配体信号协调，导致其不对称定位 受体，卷曲（FZ）蛋白质和相关的信号级联。需要核心WNT-FZ/PCP因素 解释细胞内的极性并将其转发为相邻的细胞。所有核心PCP成员都是进化 保守和调节所有PCP方面研究。该WNT-Pathway与规范的Wnt-FZ/β-Catenin不同 信号传导（并正确调节两个WNT沿通道之间的信号特异性，并被相同激活 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） FZ蛋白质的伴侣仍然了解不足。我实验室研究的重点以及该应用的重点是（i） 继续研究核心PCP信号传导因子的机械相互作用和所得的细胞 读出和细胞内反应，（ii）建立核心FZ/PCP途径之间的连接 脂肪/DS-PCP盒和（iii）（iii）是我们努力的最新补充 - 剖析纤毛的非纤维功能 两者中的蛋白质，典型的Wnt/β-catenin信号传导和Wnt/PCP途径，具有能够 在非丝状果蝇细胞中这样做。这个最近的重点来自遗传筛查，确定此类 纤毛相关因素的非丝函数。令人兴奋的正在进行的实验正在解决生理问题 FZ-和Vang-Complexes之间的调节相互作用的重要性，以及这些如何影响FZ或 Vang细胞质作用及其对PCP信号的细胞生物学反应，包括对细胞的影响 粘附和组织流动性或对细胞骨架调节的影响。另一个主要重点是基于我们 识别β-catenin核转运所需的驱动蛋白-2/IFT-A复合物。我们是 继续我们对这种令人兴奋且意外的微管相关的过程的机械解剖。 这里获取的信息将提高我们对细胞极化和作用的基本理解 在两种WNT信号途径中的睫状蛋白，还提供了对Wnt信号疾病环境的见解。