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。本申请的主要目标是评估Hedgehog（Hh）信号传导和视黄酸（RA）信号传导如何控制光感受器发育的机制模型。在该模型中，这些信号系统是共同调节的，并且平行地起作用：Hh信号传导促进视锥分化并调节RA信号传导，RA信号传导促进视杆分化并调节感光细胞表型。我们推测，Hh和RA的行为，通过影响转录因子crx和rxl/2，这反过来又调节感光细胞特异性基因的表达。我们的研究使用斑马鱼，一个强大的，在体内系统研究脊椎动物感光细胞发育的机制。通过使用允许操纵Hh和RA信号传导系统的遗传和分子工具，我们将（1）鉴定Hh信号传导在光感受器分化期间的细胞和分子靶点，（2）鉴定RA信号传导在光感受器分化期间的细胞和分子靶点，和（3）确定Hh和RA信号传导协调的机制。除了测试这些组件的机制模型，我们的实验将确定是否Hh和RA影响感光细胞的命运。 以正确比例产生多种神经元细胞类型的机制在神经生物学中提出了重要且具有挑战性的问题。该研究有望阐明Hh和RA在体内调节特定感光细胞类型发育中的各自作用。此外，类维生素A治疗作为视网膜疾病的治疗正在积极测试中，并且Hh已被建议作为特定视觉障碍的潜在治疗。进一步了解Hh和RA的作用机制，将有助于重新评估目前的治疗方法，并设计未来的治疗方法。

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.