Mosaic eyes gene is required for retinal development

描述（由申请人提供）：我们的长期目标是识别和理解参与视网膜组织、感光细胞形态发生和存活的分子和细胞途径。我们正在研究斑马鱼中的马赛克眼（莫伊）基因;莫伊的突变导致视网膜分层失败和视网膜色素上皮（RPE）缺陷。我们发现，视网膜上皮细胞也是不适当的组织;在莫伊-视网膜中，它们在整个上皮细胞中分裂，而不是局限于顶端（RPE）表面。我们通过产生遗传嵌合体表明，莫伊功能在RPE中是相邻视网膜细胞分裂的适当定位所必需的，而不是在视网膜细胞本身中所必需的（詹森等人，2001年）。 我们克隆了莫伊基因座，它编码一种新的FERM蛋白（4.1蛋白，Ezrin，Radixin，Moesin）。我们提供了初步的证据表明，莫伊作用于顶端细胞极性的碎屑途径。人Crumbs同源物1（Crbl）基因中的突变与两种严重和早发性视网膜变性疾病，视网膜色素变性12（RP 12; den霍兰德等人，1999）和Leber先天性黑蒙1（LCA 1; den霍兰德等人，2001年a）。最近的工作，使用高分辨率显微镜在体内，已经揭示了LCA 1患者的视网膜异常分层，表型非常相似的莫伊突变。 我们将检验莫伊直接与Crumbs蛋白相互作用的假设。在果蝇中，碎屑对于光感受器形态发生是必需的（Izaddoost等人，2002; Pellikka等人，2002），并且RP 12的早期和严重发作可能表明其在脊椎动物光感受器形态发生中起类似的作用。斑马鱼莫伊在视网膜中的表达与crbl相似，提示它可能与crbl在光感受器形态发生中协同作用。我们将检验莫伊是正常感光细胞形态发生所必需的假设。最后，我们将测试莫伊是正常视网膜分层所需的RPE的假设。

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.