Retina Cell-Fate Determination and Pattern Formation

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 疾病。加深对构建正常视网膜的发育机制的理解 实现这一目标所需的。我们的实验方法使用果蝇 Drosophila melanogasteras 动物模型 系统识别和确定正常视网膜过程中相互作用的保守基因和通路的功能 发展。最近的研究结果表明，果蝇和哺乳动物之间存在许多发育相似之处 视网膜。其中之一就是果蝇 R8 感光器规格与神经节细胞之间的关系 哺乳动物的测定。这些是第一个被指定的视网膜细胞，在其发育过程中表达直系同源基因。 发育，并在视网膜图案形成中发挥指导作用。我们已经证明了无意义（sens），它编码了 保守的转录因子，对于 R8 光感受器分化来说既是必要的又是充分的，并且可能发挥作用 顶部附近控制果蝇 R8 规范的遗传途径。此外，sens 的鼠同源物， Gill 在早期视网膜神经节细胞中表达，表明 sens 和 Gill 之间的功能保守性可能 也存在。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 充当表皮生长因子受体 (EGFR) 信号传导的调节剂 途径，也可能在 R8 规范期间与 Hedgehog (Hh) 信号传导配合。由于这些信号通路 也参与哺乳动物视网膜形态发生，我们提出的研究来表征感觉功能和 调控，并分离与感觉相互作用的新基因可能会为人类提供重要的见解 视网膜发育。我们的目标是： 1. 表征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调控元件并鉴定直接控制sens表达的基因。 4. 识别在眼睛发育过程中与感觉相互作用的新基因。 这些研究旨在进一步阐明控制正常视网膜的分子和遗传机制 发展。我们使用果蝇中最强大的遗传模型 R8 规范作为我们的发育系统 系统可用。由于我们研究的基因和通路在人类中高度保守，这项工作将直接 影响我们对人类视网膜发育的理解。

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 melanogasteras 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, Gill, is expressed in early retinal ganglion cells, suggesting that functional conservation between sens and Gill 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.