Regulation of Ocular Lens Development by PDZ Proteins

性状（由申请方提供）：透镜发育的调节需要多种生长因子信号通路、细胞-细胞和细胞-基质粘附复合物以及细胞周期调节剂的协调活性。一个重要的问题是如何在空间和时间上协调所有这些不同的路径，以确保正确的透镜形成。PDZ（PSD 95/DLG/ZO-1）蛋白是具有连接所有这些分子途径的潜在能力的蛋白。通过它们作为支架的能力，它们组装大型蛋白质复合物，根据组装的组成分子，向不同的细胞命运发出信号。在果蝇中，编码两种PDZ蛋白的肿瘤抑制基因Discs Large（dig）和Scribble（scrib）对于建立和维持正常上皮细胞结构、极性和增殖是必需的。我们最近的转基因小鼠的研究使用的E6癌蛋白从人乳头瘤病毒作为PDZ蛋白的显性抑制剂，提出了迄今尚未认识的PDZ蛋白，如Dlg-1和Scrib在透镜发育的许多阶段的作用。我们还表明，Dlg-1的一个亚型等位基因在胚胎发育过程中引起小鼠透镜的白内障异常。在本申请中，我们提出对Dlg-1、Scrib和其它相互作用基因中的小鼠突变体使用遗传和分子分析的组合，以（1）确定透镜发育中对Dlg-1和/或Scrib的需要，（2）确定Dlg-1和/或Scrib是否通过调节细胞粘附蛋白复合物来调节透镜发育，以及通过其调节晶状体发育的机制，和（3）确定Dlg-1和/或Scrib调节细胞周期的途径。在许多白内障病症中观察到细胞周期控制、细胞结构和极性的丧失，所述白内障病症的范围从先天性白内障到成人中的年龄相关性白内障到白内障手术后发生的继发性白内障。在胚胎发生期间调节透镜细胞的这些基本性质的因子具有与在动物的整个生命中维持正常的透镜结构和透明度相关的潜力。此外，PDZ和极性基因的缺陷最近被发现与实验动物和人类的视网膜变性有关。因此，我们从我们的新研究中获得的了解Dlg-1和Scrib在小鼠透镜发育中的作用的知识可能不仅对我们理解透镜发育而且对我们理解白内障和其他眼部疾病具有重大影响。

DESCRIPTION (provided by applicant): Regulation of lens development requires the coordinated activities of a number of growth factor signaling pathways, cell-cell and cell-matrix adhesion complexes, and cell cycle regulators. An important question is how all these different pathways are spatially and temporally coordinated so as to ensure proper lens formation. PDZ (PSD95/DLG/ZO-1) proteins are proteins that have the potential capacity to link all of these molecular pathways. Through their capacity to act as scaffolds, they assemble large protein complexes that, depending on the constituent molecules assembled, signal towards different cellular fates. In Drosophila, the tumor suppressor genes Discs Large (dig) and Scribble (scrib), which encode two PDZ proteins, are essential for establishing and maintaining normal epithelial cell structure, polarity and proliferation. Our recent transgenic mouse studies using of the E6 oncoprotein from human papillomavirus as a dominant inhibitor of PDZ proteins, suggests a heretofore unrecognized role for PDZ proteins such as Dlg-1 and Scrib in many stages of lens development. We also have shown that a hypomorphic allele of Dlg-1 gives rise to cataractous abnormalities in the mouse lens during embryogenesis. In this application, we propose to use a combination of genetic and molecular analyses on mouse mutants in Dlg-1, Scrib, and other interacting genes to (1) determine the requirements for Dlg-1 and/or Scrib in lens development, (2) determine if, and the mechanisms through which, Dlg-1 and/or Scrib regulate lens development by modulating cell adhesion protein complexes, and (3) define the pathway through which Dlg-1 and/or Scrib regulate the cell cycle. Loss of cell cycle control, cell architecture and polarity are observed in many cataractous conditions ranging from congenital cataracts to age-related cataracts in adults to secondary cataracts, that occur following cataract surgery. Factors that regulate these fundamental properties of lens cells during embryogenesis have the potential to be relevant to maintaining normal lens structure and transparency throughout the life of the animal. Additionally, defects in PDZ and polarity genes recently have been found to be associated with retinal degenerations in experimental animals and humans. Thus, the knowledge we gain from our novel studies to understand the role of Dlg-1 and Scrib in mouse lens development potentially will have significant impact on our understanding not only of lens development but also cataract, and other ocular diseases.