Wnt/Frizzled-PCP signaling in development and disease

上皮细胞的极化有两个轴，一个是普遍存在的顶端-基底极性，另一个是第二轴 在上皮平面内，称为平面细胞极性（PCP）。细胞极性和相关的有序细胞 器官发生和稳态过程中的排列和模式依赖于Wnt信号介导的PCP 机制等PCP组织的典型例子包括果蝇成虫的表皮结构，如 在哺乳动物中，五氯苯酚的显著特征是在皮肤、内耳 上皮或呼吸系统和大多数其他内部器官。此外，收敛扩张 原肠胚形成和神经管闭合过程需要Wnt/PCP信号传导。同样，五氯苯酚途径 与调节许多器官干细胞的不对称细胞分裂有关。五氯苯酚的研究 在果蝇中建立继续作为一种范例，以解开这种类型的极性发展， 人类疾病PCP由Wnt配体信号协调，导致它们的不对称定位。 受体，卷曲蛋白（Fz）和相关的信号级联。需要堆芯Wnt-Fz/PCP系数 以解释单元内的极性并将其中继到相邻单元。PCP的所有核心成员在进化上 保护和调节所研究的五氯苯酚的所有方面。该Wnt通路不同于经典的Wnt-Fz/β-连环蛋白 信号传导（以及两个Wnt途径之间的信号传导特异性的正确调节，由相同的Wnt途径激活） 受体，对发育和疾病至关重要）。影响下游极性的细胞机制 Fz或旺（哺乳动物中的Vangl 1/2）的表达，其中旺/Vangl是细胞间跨膜PCP- Fz蛋白的伴侣，仍然知之甚少。我的实验室的研究的重点，以及这个应用程序，是（i） 继续研究核心PCP信号传导因子和由此产生的细胞因子之间的相互作用机制。 读出和细胞内反应，（ii）建立核心Fz/PCP途径和细胞内反应之间的联系。 Fat/Ds-PCP盒，以及（iii）-我们最近的努力-解剖睫状体的非纤毛功能 在经典的Wnt/β-catenin信号通路和Wnt/PCP通路中， 在没有纤毛的果蝇细胞中也能做到。这一最近的焦点源于基因筛选， 纤毛相关因子的非纤毛功能。令人兴奋的正在进行的实验正在解决生理 Fz-和Vang-复合物之间的调节相互作用的意义，以及它们如何影响Fz或 旺细胞质效应子及其对PCP信号传导的细胞生物学响应，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。另一个重点是基于我们的 鉴定β-连环蛋白核转位所需的驱动蛋白-2/IFT-A复合物。我们 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解剖。 在这里获得的信息将促进我们对细胞极化和细胞分化的作用的基本理解。 纤毛蛋白在Wnt信号通路中的作用，也提供了对Wnt信号疾病背景的了解。

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.