GENETIC CONTROL OF RETINA SPECIFICATION

这项研究提案的长期目标是确定 正常视网膜发育所需保守基因的功能 人类。为此，我们使用了两个模型系统：鼠标Mus 肌肉和果蝇黑腹果蝇。这两种技术的结合 这些特性所提供的遗传和分子技术是 对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 重点关注新发现的脊椎动物同源物的功能 果蝇基因dachshund(Dac)，它编码一种核蛋白 这既是视网膜发育的必要条件，也是充分条件。 果蝇。DAC功能丧失会产生没有眼睛的苍蝇 DAC的靶向表达导致了完整和 在大多数主要的附属物上形成了正确的复眼 德罗斯皮拉。这些结果与使用 盲人基因，这是人类无虹膜的功能同源物。 此外，我们还证明了盲眼可以诱导DAC的表达和 反之亦然，这表明这些基因可能形成了一个正反馈循环 在正常的视网膜发育期间。我们已经确认了多个 DAC的脊椎动物同源物，并已开始描述这些基因的特征。 最重要的是，至少有一个小鼠DAC基因在 视网膜贯穿整个发育过程。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 也将在哺乳动物的眼睛发育过程中发挥关键作用。我们建议 具体目标如下：1.完成分子表征 小鼠和人类的DAC基因家族。2.确定的功能 小鼠DAC通过靶向干扰和异位表达。3.审查 小鼠DAC与眼睛所需其他基因的相互作用 发展。4.筛选物理上与之相互作用的蛋白质 哺乳动物和果蝇DAC蛋白。 这些实验勾勒出了一种策略，以确定 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 人类视网膜疾病的治疗方法和途径。

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.