Mosaic eyes gene is required for retinal development

描述(由申请者提供)：我们的长期目标是识别和了解与视网膜组织、光感受器形态发生和存活相关的分子和细胞途径。我们正在研究斑马鱼的马赛克眼睛(MOE)基因；MOE基因的突变会导致视网膜分层失败和视网膜色素上皮(RPE)缺陷。我们发现，视网膜上皮细胞的组织也不正确；在更多的视网膜中，它们分裂遍及整个上皮，而不是定位于视网膜根尖(RPE)表面。我们通过产生遗传马赛克表明，MOE功能是RPE中正确定位相邻视网膜细胞分裂所必需的，而不是视网膜细胞本身所必需的(Jensen等人，2001年)。 我们克隆了moe基因，并编码了一种新的酵母蛋白(4.1蛋白，Ezrin，Radioxin，Moesin)。我们提供的初步证据表明，MOE在顶端细胞极性的碎屑通路中起作用。人类Crumbs Homologue 1(Crb1)基因突变与两种严重和早期发病的视网膜变性疾病有关，视网膜色素变性12(Rp12；den Hollander等人，1999)和Leber先天性黑色素沉着症1(LCA1；den Hollander等人，2001 a)。最近在体内使用高分辨率显微镜的工作表明，LCA1患者的视网膜是异常层叠的，这种表型与MOE突变非常相似。 我们将检验MOE与Crumbs蛋白质直接相互作用的假设。在果蝇中，面包屑是光感受器形态发生所必需的(Izaddoost等人，2002；Pellikka等人，2002)，Rp12的早期和严重发作可能表明它在脊椎动物光感受器形态发生中发挥类似的作用。斑马鱼MOE在视网膜中的表达类似于crb1，提示它可能与crb1在光感受器形态发生中起协同作用。我们将检验MOE是正常光感受器形态发生所必需的假设。最后，我们将验证这样的假设，即正常的视网膜板层需要在RPE中使用MOE。

DESCRIPTION (provided by applicant): Our long-term goal is to identify and understand the molecular and cellular pathways involved in retinal organization, and photoreceptor morphogenesis and survival. We are studying the mosaic eyes (moe) gene in zebrafish; mutations in moe cause a failure of retinal lamination and defects in the retinal pigmented epithelial (RPE). We found that retinal epithelial cells are also improperly organized; in moe- retinas they divide throughout the epithelium instead of being localized to apical (RPE) surface. We showed by generating genetic mosaics that moe function is required in the RPE for the proper localization of adjacent retinal cell divisions rather then being required in the retinal cells themselves (Jensen et al., 2001). We cloned the moe locus and it encodes a novel FERM protein (for 4.1 protein, Ezrin, Radixin, Moesin). We provide preliminary evidence that moe acts in the crumbs pathway of apical cell polarity. Mutations in the human Crumbs homologue 1 (Crbl) gene are associated with two severe and early onset retinal degeneration diseases, retinitis pigmentosa 12 (RP12; den Hollander et al., 1999) and Leber's Congenital Amaurosis 1 (LCA1; den Hollander et al., 2001a). Recent work using high-resolution microscopy in vivo, has revealed that the retinas of LCA1 patients are abnormally laminated, a phenotype remarkably similar to the moe mutations. We will test the hypothesis that Moe interacts directly with Crumbs proteins. In Drosophila, crumbs is necessary for photoreceptor morphogenesis (Izaddoost et al., 2002; Pellikka et al., 2002) and the early and severe onset of RP12 may suggest it plays a similar role in vertebrate photoreceptor morphogenesis. Zebrafish moe is expressed in the retina like crbl, suggesting it may cooperate with crbl in photoreceptor morphogenesis. We will test the hypothesis that moe is required for normal photoreceptor morphogenesis. Finally, we will test the hypothesis that moe is required in the RPE for normal retinal lamination.