Patterning Genes in Retinal Development

总结/摘要 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， 资助期间已经证明了这些因素不仅对感光细胞分化的重要性， 也用于光感受器命运和光感受器维持。我们的工作提供了体内证据， 细胞外因子视黄酸（RA）影响视杆细胞和视锥细胞神经发生， 祖先此外，RA选择性地调节特定感光细胞群体的分化， 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），其是所有光感受器类型的分化所需的，并且其是 在整个生命周期内进行视锥细胞感光器维护。在建议的奖励期内，我们将在 这些研究通过评估特定的细胞外因子对感光细胞命运和分化的影响， 研究细胞选择性对参与视杆细胞和视锥细胞决定，分化， 和感光细胞病理学。我们综合运用遗传学，分子学，药理学，组织学， 计算和生物信息学工具来研究斑马鱼模型。我们将测试以下假设：1）RA Notch信号控制视杆细胞和视锥细胞的命运; 2）微环境因子RA和Hh选择性地 在感光细胞分化过程中操纵细胞特异性基因网络; 3）限制Hh的数量 在整个生命周期中的信号传导将引起光感受器损伤反应。

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.