Retina Cell-Fate Determination and Pattern Formation

描述(申请人提供)：该研究项目的长期目标是提高我们预防、诊断和治疗人类视网膜疾病的能力。为了实现这一目标，需要对用于构建正常视网膜的发育机制有更好的理解。我们的实验方法使用果蝇黑腹果蝇作为动物模型系统，以识别和确定在正常视网膜发育期间相互作用的保守基因和途径的功能。最近的发现表明，果蝇和哺乳动物的视网膜在发育上存在许多相似之处。其中一个相似之处是果蝇的R8光感受器规格与哺乳动物的神经节细胞决定之间的关系。这些细胞是第一批被指定的视网膜细胞，在它们的发育过程中表达同源基因，并在视网膜图案形成中发挥指导作用。我们已经证明，编码一种保守的转录因子的无感(SENS)对于R8光感受器的分化既是必要的也是充分的，并且很可能在控制果蝇R8规范的遗传途径的顶端附近发挥作用。此外，小鼠SENS的同源物Gfi1在早期的视网膜神经节细胞中表达，这表明SENS和Gfi1之间可能也存在功能保守。因此，我们正在研究SENS控制果蝇R8分化的机制。我们的初步数据表明，SENS作为表皮生长因子受体(EGFR)信号通路的调节器，也可能在R8规范过程中与Hedgehog(HH)信号协同作用。由于这些信号通路也参与哺乳动物视网膜的形态发生，我们提出的关于SENS功能和调控的研究，以及分离与SENS相互作用的新基因，可能会为人类视网膜的发育提供重要的见解。我们的目标是： 1.研究SENS与EGFR信号通路之间的相互作用。 2.阐明SENS与HH信号通路的关系。 3.剖析SENS调控元件，寻找直接控制SENS表达的基因。 4.确定在眼睛发育过程中与SENs相互作用的新基因。 这些研究旨在进一步阐明控制正常视网膜发育的分子和遗传机制。我们在果蝇中使用R8规范作为我们的发育系统，这是目前可用的最强大的遗传模型系统。由于我们研究的基因和途径在人类中高度保守，这项工作将直接影响我们对人类视网膜发育的理解。

DESCRIPTION (provided by applicant): The long-term goal of this research project is to improve our ability to prevent, diagnose, and treat human retinal diseases. An improved understanding of the developmental mechanisms employed to construct a normal retina is required to achieve this goal. Our experimental approach uses the fruit fly Drosophila melanogaster as an animal model system to identify and determine the function of conserved genes and pathways that interact during normal retinal development. Recent findings suggest that many developmental parallels exist between Drosophila and mammalian retina. One such parallel is the relationship between R8 photoreceptor specification in Drosophila and ganglion cell determination in mammals. These are the first retinal cells to be specified, express orthologous genes during their development, and play an instructive role in retinal patterning. We have shown that senseless (sens), which encodes a conserved transcription factor, is both necessary and sufficient for R8 photoreceptor differentiation, and is likely to act near the top the genetic pathway controlling R8 specification in Drosophila. Furthermore, the murine homolog of sens, Gfi1, is expressed in early retinal ganglion cells, suggesting that functional conservation between sens and Gfi1 may also exist. We are therefore investigating the mechanism by which sens controls R8 differentiation in Drosophila. Our preliminary data suggest that sens acts as a regulator of the Epidermal Growth Factor Receptor (EGFR) signaling pathway and may also cooperate with Hedgehog (Hh) signaling during R8 specification. Since these signaling pathways are also involved in mammalian retinal morphogenesis, our proposed studies to characterize sens function and regulation, and to isolate new genes that interact with sens are likely to provide important insights regarding human retinal development. Our Aims are to: 1. Characterize the interaction between sens and the EGFR signaling pathway. 2. Elucidate the relationship between sens and the Hh signaling pathway. 3. Dissect sens regulatory elements and identify genes directly controlling sens expression. 4. Identify new genes that interact with sens during eye development. These studies are designed to further elucidate the molecular and genetic mechanisms controlling normal retina development. We use as our developmental system R8 specification in Drosophila, the most powerful genetic model system available. Since the genes and pathways we study are highly conserved in humans, this work will directly impact our understanding of human retinal development.