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: 2331668
• 负责人: Graeme Mardon
• 金额: $ 19.25万
• 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/2331668
• 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 视网膜期间细胞命令测定和模式形成的机制 发展。仅在美国，超过3000万人 患有某种视觉障碍。在许多情况下，设计更多 有效的眼病治疗方法将大大受益于 对正常视网膜发育机制的详细知识。 在我们对脊椎动物发展的理解方面的巨大收益已有 通常来自使用模型系统的研究。最近，明确的相似之处 果蝇和脊椎动物视网膜发育之间已被辨别。 正常眼需要的三个果蝇基因的鼠同源物 已经确定了在 鼠标的眼睛。这些基因中的至少一个（果蝇无眼）是 小鼠（小眼）和人类的适当眼睛发育所必需 （Aniridia）。因此，至少某些视网膜的基本机制 从果蝇到 哺乳动物。该建议概述了一项旨在进一步的研究计划 利用果蝇作为模型系统，以识别和理解 正常视网膜发育所需的保守基因的功能。 在果蝇中，光感受器的发育发生在上皮单层中 称为眼睛想象的椎间盘。神经差异扩散在 眼盘在眼睛上皮的凹痕后称为 形态发生犁沟。这种犁沟的运动需要两个功能 保守的基因：DPP（TGFBETA同源物）和刺猬（分泌的 形态学）。我们已经表征了编码的基因腊肠犬（DAC） 正常眼发育所需的一种新型核蛋白。在 缺乏DAC功能，形态发生运动的启动 犁沟被流产，而DAC突变的成年人则没有眼睛发育。 DAC是唯一已知控制这一波的启动的基因 眼中的形态发生。对DAC基因的进一步研究可能 提供有关此保守功能的重要信息 细胞间信号通路和视网膜命令规格。我们的 具体目的是：a）确定是否会发生视网膜发展 在没有DAC功能的情况下，如果DAC足以诱发视网膜 发展; b）研究DAC在控制细胞周期中的作用； c）确定DAC突变眼表型中的角色死亡在DAC突变表型中的角色； d）将DAC放在控制视网膜的已知遗传层次结构中 发展; e）用DAC进行遗传研究以识别新型 潜在的相互作用蛋白。 DAC功能的研究可能会导致 对我们对基本机制的理解做出了重大贡献 正常的视网膜发育。