GENETIC CONTROL OF RETINA SPECIFICATION

视网膜规范的基因控制

• 批准号: 2882946
• 负责人: Graeme Mardon
• 金额: $ 21.39万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882946
• 关键词: Drosophilidae; animal genetic material tag; chimeric proteins; chromaffin cells; developmental genetics; gene expression; gene interaction; gene targeting; genetic regulation; histogenesis; human genetic material tag; immunoprecipitation; in situ hybridization; laboratory mouse; molecular cloning; nucleic acid sequence; polymerase chain reaction; protein structure function; retina; site directed mutagenesis; yeast two hybrid system

The long-term goal of this research proposal is to determine the function of conserved genes required for normal retinal development in humans. We are using two model systems toward this end: the mouse Mus musculus and the fruitfly Drosophila melanogaster. The combination of genetic and molecular techniques afforded by these specifies is of unparalleled power and importance for the development of new tools for early diagnosis and treatment of human retinal disease. Our work focuses on the function of the newly discovered vertebrate homologs of the Drosophila gene dachshund (dac), which encodes a nuclear protein that is both necessary and sufficient for retinal development in Drosophila. Loss of dac funtion produce flies with no eyes whereas targeted expression of dac leads to the development of complete and properly formed compound eyes on most of the major appendages of Drospohila. These results are very similar to those observed with the eyeless gene, which is a functional homolog of human Aniridia. Moreover, we have shown that eyeless induces dac expression and vice versa, suggesting that these genes may form a positive feedback loop during normal retinal development. We have identified multiple vertebrate homologs of dac and have begun to characterize these genes. Most significantly, at least one mouse Dac gene is expressed in the retina throughout development. Given the highly conserved nature of retinal development, it is very likely that the vertebrate Dac genes will also play critical roles in eye development in mammals. We propose the following Specific Aims: 1. Complete the molecular characterization of the mouse and human Dac gene families. 2. Determine the function of mouse Dac by targeted disruption and ectopic expression. 3. Examine interactions between mouse Dac and other genes required for eye development. 4. Screen for proteins that physically interact with mammalian and Drosophila Dac proteins. These experiments outline a strategy to determine the function of the highly conserved Dac gene in mammalian retinal development and are likely to provide valuable information regarding the production of new therapies and approaches for the treatment of human retinal disease.

这项研究计划的长期目标是确定 正常视网膜发育所需的保守基因的功能 人类 为此，我们使用了两种模型系统： musculus和果蝇Drosophila melanogaster。 的组合 这些规定所提供的遗传和分子技术是 开发新工具的无与伦比的力量和重要性 人类视网膜疾病的早期诊断和治疗。 我们的工作 重点是新发现的脊椎动物同源物的功能， 果蝇基因dachshund（dachshund），编码一种核蛋白 这是视网膜发育所必需的， 果蝇 失去嗅觉功能会产生没有眼睛的苍蝇， 有针对性的表达ESTs导致发育完整的， 在大多数的主要附肢上都有适当形成的复眼 Drospohila 这些结果与使用 eyeless基因是人类无虹膜的功能同源物。 此外，我们已经表明，无眼诱导表达和副 反之亦然，这表明这些基因可能形成一个正反馈回路， 在正常的视网膜发育过程中。 我们发现了多个 脊椎动物的同源基因，并已开始表征这些基因。 最重要的是，至少一个小鼠Dac基因在小鼠的细胞中表达。 视网膜在整个发育过程中。 鉴于其高度保守的性质， 视网膜发育，很可能是脊椎动物的Dac基因 在哺乳动物的眼睛发育中也起着关键作用。 我们提出 具体目标如下：1。完成分子表征 小鼠和人类Dac基因家族。2.确定的功能 小鼠Dac的靶向破坏和异位表达。 3.审查 小鼠Dac和眼睛所需的其他基因之间的相互作用 发展4.筛选与蛋白质相互作用的蛋白质 哺乳动物和果蝇Dac蛋白。 这些实验概述了一种策略，以确定的功能， 在哺乳动物视网膜发育中高度保守的Dac基因， 可能提供有关新产品生产的有价值的信息 用于治疗人视网膜疾病的疗法和方法。