Interactions of planar polarity and the cytoskeleton

上皮细胞相对于其顶-基底轴以及在上皮平面内的极化对于适当的器官功能是至关重要的。上皮平面细胞极性（Epithelial planar cell polarity，PCP）是人类和昆虫上皮细胞的特征。例如，它在果蝇的高度结构化的复眼和翅毛上，以及在鱼的鳞片或哺乳动物的内耳中可见。内耳和前庭系统的感觉细胞产生一系列精确有序的静纤毛，它们的长度和排列都是确定的。影响静纤毛形成和定向的遗传性疾病导致耳聋和平衡问题。果蝇体内形成五氯苯酚的遗传网络与人类和小鼠体内的遗传网络非常相似。vangl 2、celsr 1和myosinVIIA等基因或其果蝇同源基因stbm、fmi和zipper的突变都会影响五氯苯酚。短的世代时间和强大的遗传和分子工具使果蝇成为鉴定PCP信号组分的理想工具，高度保守性使这些基因极有可能在脊椎动物中也发挥相应的作用。在PCP信号传导过程中，上皮细胞将信号转化为位置信息，并修改其细胞骨架装置，以移动或产生适当定向的结构。 我们将研究非经典的Fz信号通路，已被证明在这一过程中发挥核心作用，其信号活性是精确调节的组件，如stbm/vangl 2。我们将1）精确表征Stbm的蛋白质相互作用并定义其机制作用，2）使用分子和遗传方法的组合识别将PCP信号传导与细胞形状和细胞骨架变化联系起来的缺失组件。从果蝇获得的信息将用于设计小鼠内耳系统的实验，该实验将与M。NIDCD的Kelley因此，将我们的发现扩展到哺乳动物的耳朵发育是可能的。

Polarization of epithelial cells with respect to their apical-basal axis as well as within the plane of the epithelium is crucial for proper organ function. Epithelial planar cell polarity (PCP) is characteristic for epithelia of species as diverse as humans and insects. For example, it is visible in the highly structured compound eye and on wing hairs of Drosophila, as well as on the scales of fish or in the mammalian inner ear. Sensory cells of the inner ear and the vestibular system produce an exquisite array of ordered stereocilia of defined length and arrangement. Genetic diseases affecting stereocilia formation and orientation lead to deafness and balance problems. The genetic network responsible for PCP establishment in Drosophila is very similar to those in humans and mice. Mutations in genes such as vangl2, celsr1 and myosinVIIA or their fly homologs stbm, fmi and zipper, all affect PCP. The short generation time and the powerful genetic and molecular tools available make Drosophila ideal for identifying components of PCP signaling, and the high degree of conservation makes it extremely likely these genes will also have corresponding roles in vertebrates. During PCP signaling, epithelial cells convert signals into positional information and modify their cytoskeletal apparatus in order to move or produce properly oriented structures. We will study the non-canonical Fz signaling pathway that has been shown to play a central role in this process and whose signaling activity is precisely regulated by components such as stbm/vangl2. We will 1) precisely characterize protein interactions of Stbm and define their mechanistic role and 2) identify missing components linking PCP signaling to changes in cell shape and the cytoskeleton using a combination of molecular and genetic approaches. The information gained from Drosophila will be used to design experiments in the mouse inner ear system that will be performed in collaboration with Dr. M. Kelley at the NIDCD. It will, therefore, be possible to extend our discoveries to mammalian ear development.