Patterning Genes in Retinal Development

摘要/摘要 这项拟议研究的长期目标是确定细胞和分子事件 导致脊椎动物视网膜中特定细胞类型的分化。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 资助期表明，这些因素不仅对光感受器分化具有重要意义，而且 也用于光感受器的命运和光感受器的维护。我们的工作提供了活体证据 视网膜晚期供应细胞外因子维甲酸(RA)影响视杆细胞与视锥细胞的神经发生 祖先。此外，RA选择性地调节特定光感受器群体的分化 在视网膜发育后期提供。这些调节功能与细胞外的调节功能不同 Hedgehog因子(HH)，它是区分所有感光细胞类型所必需的，也是必需的 在视锥感光器维护的整个寿命内。在拟议的授权期内，我们将在 这些研究通过评估特定的细胞外因素对感光细胞的命运和分化的影响， 检测细胞对参与视杆细胞和视锥细胞决定、分化、 在光感受器病理学中。我们综合运用了遗传学、分子、药理学、组织学、 斑马鱼模型的计算、生物信息学工具。我们将检验以下假设：1)RA 和Notch信号控制棒VS锥体命运；2)微环境因子RA和HH选择性 在感光细胞分化过程中操纵细胞特有的基因网络；以及3)限制HH的数量 在整个生命周期中，信号会引发光感受器损伤反应。

SUMMARY/ABSTRACT 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.