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，无处不在的尖端-基底端和第二轴 在上皮平面内，称为平面细胞极性(PCP)。细胞极性和相关有序细胞 Wnt信号介导的PCP在器官发生和动态平衡中的排列和模式 机制。五氯苯酚组织的经典例子包括果蝇成体角质层结构，如 翅膀和胸腔上皮，以及哺乳动物中PCP的显著方面，在皮肤、内耳中很明显。 上皮，或呼吸系统和大多数其他内脏。此外，收敛扩张 原肠发育和神经管闭合过程需要Wnt/PCP信号。同样，五氯苯酚途径 与调节许多器官的干细胞中的不对称细胞分裂有关。五氯苯酚的研究 在果蝇中的建立继续作为一个范例，以解开这种类型的发育和 人类疾病。PCP被Wnt配体信号所协调，导致其不对称定位 受体、FrizzledFZ蛋白和相关的信号级联反应。核心WNT-FZ/PCP系数是必需的 来解释细胞内的极性并将其传递给邻近的细胞。所有核心的PCP成员都在进化中 保存和调节所研究的所有PCP方面。这个Wnt途径不同于经典的Wnt-Fz/β-连环蛋白 信号(以及两个Wnt-通路之间的信号特异性的正确调节，由相同的 受体(S)，对发育和疾病至关重要)。影响下游极性的细胞机制(S) Fz或Vang(哺乳动物中的Vangl1/2)，Vang/Vang1是细胞间跨膜PCP-1。 FZ蛋白的合作伙伴，仍然知之甚少。我的实验室的研究和这项应用的重点是(I) 继续研究核心PCP信号因子和由此产生的细胞之间的机制相互作用 读出和细胞内反应，(Ii)建立核心FZ/PCP途径和 FAT/DS-PCP盒，和(Iii)-我们最近的一项努力-解剖睫状体的非睫状体功能(S) 蛋白质在经典的Wnt/β-连环蛋白信号通路和Wnt/PCP通路中，具有能够 在没有纤毛的果蝇细胞中这样做。最近的关注源于基因筛查，识别出这样的 纤毛非纤毛功能的相关因素。令人兴奋的正在进行的实验正在解决生理上的 Fz-和Vang-复合体之间调节相互作用的意义，以及这些相互作用如何影响Fz或 Vang胞质效应因子及其对PCP信号的细胞生物学反应，包括对细胞的影响 黏附和组织流动性，或其对细胞骨架调节的影响。另一个主要关注点是我们的 鉴定β-连环蛋白核转位所需的Kinesin-2/IFT-A复合体。我们是 继续我们对这一令人兴奋和意想不到的微管相关过程的机械剖析。 在这里获得的信息将促进我们对细胞极化和细胞周期蛋白的作用的基本理解 纤毛蛋白在任一WNT信号通路中，也提供了对WNT信号疾病背景的洞察。