Retina Cell-Fate Determination and Pattern Formation

描述（由申请人提供）：本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，需要更好地了解构建正常视网膜的发育机制。我们的实验方法使用果蝇作为动物模型系统来识别和确定在正常视网膜发育过程中相互作用的保守基因和途径的功能。最近的研究结果表明，果蝇和哺乳动物的视网膜在发育上有许多相似之处。其中一个类似的例子是果蝇的R8光感受器与哺乳动物的神经节细胞测定之间的关系。这是第一批被指定的视网膜细胞，在其发育过程中表达同源基因，并在视网膜模式中起指导作用。我们已经证明，编码保守转录因子的sens对于R8光感受器分化是必要和充分的，并且可能在果蝇中控制R8规范的遗传途径的顶部附近起作用。此外，sens的小鼠同源物Gfi1在早期视网膜神经节细胞中表达，这表明sens和Gfi1之间可能存在功能守恒。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）信号通路的调节剂，也可能在R8规范过程中与Hedgehog （Hh）信号通路合作。由于这些信号通路也参与哺乳动物视网膜的形态发生，我们提出的研究表征感官功能和调控，并分离与感官相互作用的新基因，可能为人类视网膜发育提供重要的见解。我们的目标是：

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.