Patterning the retina for color vision

为色彩视觉设计视网膜图案

• 批准号: 7920045
• 负责人: Claude Desplan
• 金额: $ 34.3万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7920045
• 关键词: Activin Receptor; Activins; Address; Animals; Axon; Cells; Color; Color Visions; Discrimination; Drosophila genus; Ensure; Event; Exclusion; Eye; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Epistasis; Genetic Screening; Growth; Human; Insulin; Lead; Ligands; Light; Maintenance; Mediating; Mitotic; Optic Lobe; Optics; Output; Papio; Pathway interactions; Pattern; Photoreceptors; RNA Interference; Receptor Gene; Retina; Retinal; Retinal Cone; Rhodopsin; Role; Sensory; Sensory Receptors; Signal Pathway; Signal Transduction; Specific qualifier value; Tertiary Protein Structure; To specify; Tumor Suppression; Tumor Suppressor Proteins; UV sensitive; Work; absorption; chromatin remodeling; fly; fovea centralis; gene repression; melting; promoter; public health relevance; receptor; response; transcription factor

DESCRIPTION (provided by applicant): In order to achieve true color vision, animals need to compare the outputs of photoreceptors that are sensitive to different colors. Humans are trichromats who use Blue (S), Green (M) and Red (L) cone photoreceptors in the fovea to discriminate colors. In Drosophila, comparison occurs between the two inner photoreceptors, R7 and R8, which point in the same direction in each ommatidium (unit eye). In fact, the fly retina is composed of two classes of distinct ommatidia, which are distributed randomly throughout the retina and specialize in discriminating among different colors. 30% of ommatidia are p, which contain a UV-sensitive Rhodopsin photopigment (Rh3) in the R7 cell and blue-Rh5 in R8 and can best discriminate among short wavelengths. In the remaining 70% y ommatidia, R7 contains UV-Rh4 while R8 contains green-Rh6; they specialize in the discrimination of longer wavelengths. Because Rh3 is always associated with Rh5 and Rh4 with Rh6, this indicates that there is a signal between R7 and R8 that coordinates Rhodopsin expression. This proposal offers to study a three-step pathway that leads to the precise specification of the two classes of p and y R8. First, a BMP/Dpp signal from pR7 instructs pR8 to express Rh5. The signal is mediated by the receptor for another related growth control pathway, the Activin receptor, suggesting that the BMP and Activin pathways cross-interact. Second, a bi-stable loop insures that an unambiguous decision is made to express either Rh6 (y) or Rh5 (p). Interestingly, this loop involves the Hippo/Warts tumor suppressor pathway and the growth regulator Melted, which is part of the Insulin/TOR pathway. Thus, these tumor suppressor pathways are re-utilized in post-mitotic photoreceptors after they are no longer needed to control proliferation. Finally, maintenance of the two distinct fates is mediated by the Rhodopsin molecules themselves that act to avoid co-expression of Rhodopsins of different sensitivity. This proposal offers to study the non-canonical interaction between the BMP/Dpp and Activin pathways. It will also dissect the tumor suppressor pathway that stabilizes the decision in R8 and the involvement of Rhodopsins in maintaining the exclusive expression of one Rhodopsin gene per photoreceptor. Finally, a genetic screen using RNAi lines will identify the transcription factors that mediate the function of these signaling pathways and allow precise expression of Rhodopsins. This work has clear relevance to our understanding of retinal patterning but also of the Hippo/Warts tumor suppressor pathway whose upstream components and transcriptional effectors remain unknown. Genetics offers the best chance to identify these new components. PUBLIC HEALTH RELEVANCE: This project addresses several fundamental questions, not only about retinal patterning but also about the function of tumor suppressor and growth control pathways. We anticipate that we will be able to provide critical identification of upstream and downstream components of these pathways, in particular their output at the level of gene expression, as well as an understanding of their cross-interactions.

描述（由申请人提供）：为了实现真实的色觉，动物需要比较对不同颜色敏感的光感受器的输出。人类是三色视觉者，利用中央凹中的蓝色 (S)、绿色 (M) 和红色 (L) 视锥细胞感光器来辨别颜色。在果蝇中，比较发生在两个内部感光器 R7 和 R8 之间，它们在每个小眼（单位眼）中指向相同的方向。事实上，苍蝇视网膜由两类不同的小眼组成，它们随机分布在整个视网膜中，专门区分不同的颜色。 30% 的小眼为 p，其 R7 细胞中含有紫外线敏感的视紫红质感光色素 (Rh3)，R8 细胞中含有蓝色-Rh5，可以最好地区分短波长。其余 70% y 小眼中，R7 含有 UV-Rh4，而 R8 含有 green-Rh6；他们专注于辨别较长波长。因为Rh3总是与Rh5相关，而Rh4总是与Rh6相关，这表明R7和R8之间存在协调视紫红质表达的信号。该提案提出研究一个三步途径，从而精确指定两类 p 和 y R8。首先，来自 pR7 的 BMP/Dpp 信号指示 pR8 表达 Rh5。该信号由另一种相关生长控制途径的受体（激活素受体）介导，表明 BMP 和激活素途径存在交叉相互作用。其次，双稳态循环确保做出明确的决定来表达 Rh6 (y) 或 Rh5​​ (p)。有趣的是，这个循环涉及 Hippo/Warts 肿瘤抑制途径和生长调节剂 Melted，后者是胰岛素/TOR 途径的一部分。因此，这些肿瘤抑制途径在不再需要控制增殖后在有丝分裂后光感受器中被重新利用。最后，两种不同命运的维持是由视紫红质分子本身介导的，其作用是避免不同敏感性的视紫红质的共表达。该提案旨在研究 BMP/Dpp 和激活素通路之间的非典型相互作用。它还将剖析稳定 R8 决策的肿瘤抑制途径，以及视紫红质在维持每个光感受器一个视紫红质基因的唯一表达中的参与。最后，使用 RNAi 系的遗传筛选将鉴定介导这些信号通路功能并允许视紫红质精确表达的转录因子。这项工作与我们对视网膜图案的理解以及 Hippo/Warts 肿瘤抑制途径的理解有明显的相关性，该途径的上游成分和转录效应子仍然未知。遗传学提供了识别这些新成分的最佳机会。公共健康相关性：该项目解决了几个基本问​​题，不仅涉及视网膜模式，还涉及肿瘤抑制和生长控制途径的功能。我们预计我们将能够对这些途径的上游和下游成分进行关键鉴定，特别是它们在基因表达水平上的输出，以及对其交叉相互作用的理解。