Regulation of Ocular Lens Development by PDZ Proteins

描述（由申请人提供）：晶状体发育的调节需要许多生长因子信号通路、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动。一个重要的问题是，所有这些不同的路径如何在空间和时间上协调，以确保正确的晶状体形成。PDZ （PSD95/DLG/ZO-1）蛋白具有连接所有这些分子途径的潜在能力。通过它们作为支架的能力，它们组装大的蛋白质复合物，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disc Large （dig）和Scribble （scrib）对于建立和维持正常上皮细胞结构、极性和增殖至关重要。我们最近的转基因小鼠研究使用来自人乳头瘤病毒的E6癌蛋白作为PDZ蛋白的显性抑制剂，表明PDZ蛋白如dgl -1和Scrib在晶状体发育的许多阶段中具有迄今未被认识到的作用。我们还发现，在胚胎发生过程中，Dlg-1的一个亚型等位基因会引起小鼠晶状体的白内障异常。在本应用中，我们建议对小鼠突变体Dlg-1、Scrib和其他相互作用基因进行遗传和分子分析，以：(1)确定晶状体发育对Dlg-1和/或Scrib的要求，(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晶状体发育，以及通过何种机制，以及(3)确定Dlg-1和/或Scrib调节细胞周期的途径。在白内障手术后发生的先天性白内障、成人年龄相关性白内障和继发性白内障等许多白内障疾病中，都观察到细胞周期控制、细胞结构和极性的丧失。在胚胎发生过程中调节晶状体细胞这些基本特性的因素可能与在动物的整个生命周期中维持正常的晶状体结构和透明度有关。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知识，了解dgl -1和Scrib在小鼠晶状体发育中的作用，不仅对我们对晶状体发育的理解，而且对白内障和其他眼部疾病的理解都有重要的影响。

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.