Patterning Genes in Retinal Development

描述(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。我们继续强调细胞外因子在调节光感受器多样性和分化中的作用，因为当前资金时期的工作已经证明，这些因素不仅对光感受器分化，而且对光感受器命运和光感受器维持都具有重要意义。我们的工作提供了体内证据，证明当提供给视网膜晚期祖细胞时，细胞外因子维甲酸(RA)影响视杆细胞与视锥细胞的神经发生。此外，视黄酸在视网膜发育后期提供时，选择性地调节特定光感受器群体的分化。这些调节功能与细胞外因子Hedgehog(HH)不同，细胞外因子Hedgehog(HH)是分化所有光感受器类型所必需的，也是锥状光感受器维持整个生命周期所必需的。在拟议的获奖期内，我们将通过评估特定的细胞外因素对光感受器的命运和分化的影响，检查细胞对参与视杆和视锥决定、分化和光感受器病理的基因网络的选择效应，来建立这些研究。我们将遗传学、分子、药理学、组织学、计算学和生物信息学的工具应用到斑马鱼模型中。我们将测试以下假设：1)RA和Notch信号控制棒与锥体命运；2)微环境因子RA和HH在光感受器分化过程中选择性地操纵细胞特有的基因网络；以及3)在整个生命周期中限制数量的HH信号将参与光感受器损伤反应。公共卫生相关性：视觉功能需要一组不同的、但安排得当的专门细胞的协作活动。我们的目标是了解光感受器细胞发育和存活的机制，光感受器细胞是视觉功能所必需的，在许多视觉退行性疾病中丢失。我们的发现将应用于开发光感受器替代策略和光感受器生存疗法，以及预防和治疗视网膜发育异常。

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. We continue our emphasis on the roles of extracellular factors in regulating photoreceptor diversity and differentiation, as the work of the current funding period has demonstrated the significance of these factors not only for photoreceptor differentiation, but also for photoreceptor fate and for photoreceptor maintenance. Our work has provided in vivo evidence that the extracellular factor retinoic acid (RA) influences rod vs. cone neurogenesis when supplied to late retinal progenitors. In addition, RA selectively regulates the differentiation of specific photoreceptor populations when supplied later in retinal development. These regulatory functions are distinct from those of the extracellular factor Hedgehog (Hh), which is required for differentiation of all photoreceptor types, and which is required throughout the lifespan for cone photoreceptor maintenance. In the proposed award period, we will build on these studies through the evaluation of specific extracellular factors on photoreceptor fate and differentiation, examining cell-selective effects on networks of genes involved in rod and cone determination, differentiation, and in photoreceptor pathology. We apply a combination of genetic, molecular, pharmacological, histological, computational, and bioinformatics tools to the zebrafish model. We will test the following hypotheses:1) that RA and Notch signaling control rod vs. cone fate; 2) that the microenvironmental factors RA and Hh selectively manipulate cell-specific gene networks during photoreceptor differentiation; and 3) that limiting quantities of Hh signaling throughout the lifespan will engage a photoreceptor damage response. PUBLIC HEALTH RELEVANCE: Visual function requires the collaborative activities of a diverse, but properly arranged collection of specialized cells. Our goal is to understand the mechanisms that underlie the development and survival of photoreceptor cells, which are required for visual function, and which are lost in many visual degenerative diseases. Our findings will have applications for the development of photoreceptor replacement strategies and photoreceptor survival therapies, as well as for the prevention and treatment of developmental abnormalities of the retina.