Retina Cell-Fate Determination and Pattern Formation

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作为动物模型系统，以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，果蝇和哺乳动物视网膜之间存在许多发育相似之处。一个这样的平行关系是R8感光细胞规格在果蝇和神经节细胞决定在哺乳动物之间的关系。这些是第一个被指定的视网膜细胞，在其发育过程中表达orthopathic基因，并在视网膜图案中发挥指导作用。我们已经表明，无意义（sens），它编码一个保守的转录因子，是必要的和足够的R8感光细胞分化，并可能采取行动的顶部附近的遗传途径控制R8规格在果蝇。此外，sens的小鼠同源物Gfi1在早期视网膜神经节细胞中表达，表明sens和Gfi1之间也可能存在功能保守性。因此，我们正在调查的机制，其中sens控制R8在果蝇的分化。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，也可能与刺猬（Hh）信号在R8的规范。由于这些信号通路也参与了哺乳动物视网膜形态发生，我们提出的研究，以表征sens的功能和调节，并分离新的基因，与sens相互作用，可能会提供重要的见解有关人类视网膜发育。我们的目标是： 1.表征sens和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.