Wnt/Frizzled-PCP signaling in development and disease

上皮细胞在两个轴上极化，为其功能，普遍存在的顶-基极性和第二个轴

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.