Patterning Genes in Retinal Development

描述（由申请人提供）：拟议研究的长期目标是确定导致脊椎动物视网膜中特定细胞类型分化的细胞和分子事件。当前应用的主要目标是评估Hedgehog （Hh）信号和视黄酸（RA）信号如何控制光感受器发育的机制模型。在这个模型中，这些信号系统是共同调节的，并且是并行的：Hh信号传导锥体分化并调节RA信号传导，RA信号传导杆状细胞分化并调节光感受器表型。我们假设Hh和RA通过影响转录因子crx和rxl/2的表达而起作用，而转录因子crx和rxl/2反过来调节光受体特异性基因的表达。我们的研究使用斑马鱼，一个强大的，在体内的系统来研究脊椎动物光感受器的发育机制。通过使用允许操纵Hh和RA信号系统的遗传和分子工具，我们将(1)识别光感受器分化过程中Hh信号的细胞和分子靶标，(2)识别光感受器分化过程中RA信号的细胞和分子靶标，以及(3)确定Hh和RA信号协调的机制。除了测试这些机制模型的组成部分，我们的实验将确定Hh和RA是否影响感光细胞的命运。

DESCRIPTION (provided by applicant): The long-range objective of the proposed research is to determine the cellular and molecular events that lead to the differentiation of specific cell types in the vertebrate retina. The primary goal of the current application is to evaluate a mechanistic model for how Hedgehog (Hh) signaling and retinoic acid (RA) signaling control photoreceptor development. In this model, these signaling systems are co-regulated and act in parallel: Hh signaling propagates cone differentiation and regulates RA signaling, and RA signaling propagates rod differentiation and regulates photoreceptor phenotype. We hypothesize that Hh and RA act by influencing expression of the transcription factors crx and rxl/2, which in turn regulate photoreceptor-specific gene expression. Our research uses the zebrafish, a powerful, in vivo system for studying the mechanisms of vertebrate photoreceptor development. Through the use of genetic and molecular tools that allow the manipulation of the Hh and RA signaling systems, we will (1) identify cellular and molecular targets of Hh signaling during photoreceptor differentiation, (2) identify cellular and molecular targets of RA signaling during photoreceptor differentiation, and (3) determine the mechanism by which Hh and RA signaling are coordinated. In addition to testing these components of the mechanistic model, our experiments will determine whether Hh and RA influence photoreceptor cell fate. The mechanisms that generate multiple neuronal cell types in the correct ratios present important and challenging issues in neurobiology. The proposed research is expected to elucidate the respective roles of Hh and RA in regulating development of specific photoreceptor types in vivo. Furthermore, retinoid treatment is under active testing as a therapy for retinal disease, and Hh has been suggested as a potential treatment for specific visual disorders. An improved understanding of the mechanisms of action of Hh and RA will be valuable for reassessing current treatments, and for designing future therapies.