RETINA CELL FATE DETERMINATION AND PATTERN FORMATION

视网膜细胞命运的决定和模式的形成

• 批准号: 2654669
• 负责人: Graeme Mardon
• 金额: $ 20.02万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2000-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2654669
• 关键词: DNA binding protein; Drosophilidae; alternatives to animals in research; apoptosis; cell cycle; cell growth regulation; cyclins; developmental genetics; developmental neurobiology; gene expression; gene interaction; gene mutation; homeobox genes; imaginal disc; immunocytochemistry; larva; molecular cloning; mutant; neurogenesis; phenotype; reporter genes; retina; scanning electron microscopy; stress proteins; visual photoreceptor

The long-term goal of this project is to understand the molecular mechanisms of cell-fate determination and pattern formation during retina development. In the United States alone, more than 30 million people suffer from some type of visual disorder. In many cases, designing more effective methods of treatment for eye disease would greatly benefit from a detailed knowledge of the mechanisms of normal retinal development. Substantial gains in our understanding of vertebrate development have often come from studies using a model system. Recently, clear similarities between Drosophila and vertebrate retinal development have been discerned. Murine homologs of three Drosophila genes required for normal eye development have been identified that are specifically expressed in the mouse eye anlage. At least one of these genes (Drosophila eyeless) is required for proper eye development in both mice (small eye) and humans (Aniridia). Thus, at least some of the basic mechanisms of retinal development may have been conserved across phylogeny, from Drosophila to mammals. This proposal outlines a research plan designed to further exploit Drosophila as a model system to identify and understand the function of conserved genes required for normal retinal development. In Drosophila, photoreceptor development occurs in an epithelial monolayer called the eye imaginal disc. Neural differentiation spreads across the eye disc following an indentation in the eye epithelium termed the morphogenetic furrow. Movement of this furrow requires the function of two conserved genes: dpp (a TGFbeta homolog) and hedgehog (a secreted morphogen). We have characterized the gene dachshund (dac), which encodes a novel nuclear protein that is required for normal eye development. In the absence of dac function, initiation of movement of the morphogenetic furrow is aborted and dac mutant adults therefore develop with no eyes. dac is the only gene known to control initiation of this wave of morphogenesis in the eye. Further study of the dac gene is likely to provide important information concerning the function of this conserved intercellular signaling pathway and retinal cell-fate specification. Our specific aims are to: A) Determine whether retinal development can occur in the absence of dac function and if dac is sufficient to induce retinal development; B) Investigate the role of dac in control of the cell cycle; C) Determine what role cell-death plays in the dac mutant eye phenotype; D) Place dac in the known genetic hierarchy controlling retinal development; and E) Conduct genetic studies with dac to identify novel potential interacting proteins. Study of dac function is likely to make significant contributions to our understanding of fundamental mechanisms of normal retinal development.

该项目的长期目标是了解分子 视网膜细胞命运决定和模式形成的机制 发展。仅在美国就有超过 3000 万人 患有某种类型的视觉障碍。在很多情况下，设计更多 治疗眼病的有效方法将大大受益 对正常视网膜发育机制的详细了解。 我们对脊椎动物发育的理解取得了实质性进展 通常来自使用模型系统的研究。最近，明显的相似之处 果蝇和脊椎动物的视网膜发育之间的关系已经被辨别出来。 正常眼睛所需的三种果蝇基因的鼠同源物 已确定的发展具体体现在 鼠眼原基。这些基因（果蝇无眼）中至少有一个是 小鼠（小眼睛）和人类的眼睛正常发育所需 （阿尼瑞迪亚）。因此，至少视网膜的一些基本机制 从果蝇到 哺乳动物。该提案概述了一项研究计划，旨在进一步 利用果蝇作为模型系统来识别和理解 正常视网膜发育所需的保守基因的功能。 在果蝇中，光感受器发育发生在单层上皮中 称为眼成虫盘。神经分化遍布全身 眼盘上皮上有一个凹痕，称为“眼盘” 形态发生沟。该沟槽的移动需要两个功能 保守基因：dpp（TGFbeta同源物）和hedgehog（分泌型 形态发生素）。我们已经鉴定了腊肠犬 (dac) 基因的特征，该基因编码 正常眼睛发育所需的一种新型核蛋白。在 dac 功能缺失，形态发生运动启动 犁沟流产，dac 突变成虫因此发育成没有眼睛。 dac 是唯一已知控制这一波的启动的基因 眼睛的形态发生。对 dac 基因的进一步研究可能会 提供有关该保守功能的重要信息 细胞间信号传导途径和视网膜细胞命运规范。我们的 具体目标是： A) 确定视网膜是否会发育 在缺乏 dac 功能且 dac 足以诱导视网膜 发展; B) 研究dac在细胞周期控制中的作用； C) 确定细胞死亡在 dac 突变眼表型中起什么作用； D) 将 dac 置于已知的控制视网膜的遗传等级中 发展; E) 使用 dac 进行基因研究，以确定新的 潜在的相互作用蛋白质。对 dac 功能的研究可能使 对我们理解基本机制做出了重大贡献 视网膜的正常发育。