Patterning the retina for color vision

描述（由申请人提供）：为了实现真正的色觉，动物需要比较对不同颜色敏感的光感受器的输出。人类是三色视者，其使用中央凹中的蓝色（S）、绿色（M）和红色（L）锥状光感受器来辨别颜色。在果蝇中，比较发生在两个内部光感受器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，果蝇的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上，专门用于区分不同的颜色。30%的小眼是p，其在R7细胞中含有UV敏感的视紫红质色素（Rh 3），在R8细胞中含有蓝-Rh 5，并且可以最好地区分短波长。在剩下的70%的yommatidia中，R7含有UV-Rh 4，而R8含有绿色-Rh 6;它们专门区分较长的波长。因为Rh 3总是与Rh 5相关联，Rh 4总是与Rh 6相关联，这表明在R7和R8之间存在协调视紫红质表达的信号。该建议提供了一个三步的途径，导致两个类的p和y R8的精确规格的研究。首先，来自pR 7的BMP/Dpp信号指示pR 8表达Rh 5。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和激活素途径交叉相互作用。第二，双稳态循环确保做出明确的决定来表达Rh 6（y）或Rh 5（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，这是胰岛素/TOR途径的一部分。因此，这些肿瘤抑制途径在有丝分裂后的光感受器中被重新利用，因为它们不再需要控制增殖。最后，两种不同命运的维持是由视紫红质分子本身介导的，所述视紫红质分子本身起作用以避免不同敏感性的视紫红质的共表达。该建议提供了研究BMP/Dpp和激活素通路之间的非经典相互作用。它还将剖析肿瘤抑制途径，稳定的决定，在R8和参与视紫红质在维持一个视紫红质基因每个光感受器的排他性表达。最后，使用RNAi株系的遗传筛选将鉴定介导这些信号通路功能的转录因子，并允许视紫红质的精确表达。这项工作有明确的相关性，我们的理解视网膜图案，但也河马/疣肿瘤抑制通路的上游组件和转录效应仍然未知。遗传学提供了识别这些新成分的最佳机会。公共卫生相关性：该项目解决了几个基本问题，不仅关于视网膜图案，而且关于肿瘤抑制和生长控制途径的功能。我们预计，我们将能够提供这些途径的上游和下游组件的关键识别，特别是它们在基因表达水平上的输出，以及它们的交叉相互作用的理解。

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.