Cell Proliferation/Differentiation in Developing Retina

描述(申请人提供)：细胞的增殖和分化在正常的视网膜发育过程中受到协调调节。然而，控制细胞增殖和分化的分子机制尚不清楚。这项资助的目的是研究发育信号通路和细胞内在转录因子在果蝇视网膜发育过程中控制细胞生长、增殖和分化的机制。果蝇发育中的视网膜非常适合于所提出的研究，因为果蝇系统中有很好地描述了细胞生长、增殖和分化的区域，以及不同信号通路和细胞内在转录因子的特征区域，并且因为在果蝇系统中有大量可用的工具。 Notch信号是一种保守的发育信号通路，在眼睛发育过程中发挥着从细胞增殖、分化到决定细胞命运的多种作用。有趣的是，Notch信号在视网膜发育的不同区域的激活会导致不同的结果：Notch信号在发育中的视网膜前部诱导细胞生长和增殖，但在形态发生沟之前的细胞诱导分化。我们假设Notch信号在视网膜发育的不同区域诱导其靶点表达的不同能力是由Notch与其他信号通路或区域特异性因子之间的相互作用控制的，并且不同的靶点的表达介导了Notch信号在诱导视网膜不同区域的细胞增殖或分化中的不同作用。为了验证这些假说并阐明在发育中的视网膜中控制细胞增殖和分化的机制，我们有以下三个具体的目的：(1)研究Notch信号调节发育中的视网膜细胞周期的分子机制；(2)研究Notch信号促进细胞生长和增殖的能力被控制的机制；(3)研究在果蝇发育中视网膜中ATO表达的启动受到控制的机制。 我们的长期目标是深入了解视网膜发育过程中的细胞增殖和分化，这可能会导致开发新的方法来预防、诊断和治疗视网膜疾病以及其他存在细胞增殖或分化缺陷的人类疾病。

DESCRIPTION (provided by applicant): Cell proliferation and differentiation is coordinately regulated during normal retinal development. However, the molecular mechanisms by which cell proliferation and differentiation are controlled are not known. The goal of this grant is to investigate the mechanisms by which developmental signaling pathways and cell intrinsic transcription factors interact in the control of cell growth, proliferation and differentiation in the Drosophila developing retina. The Drosophila developing retina is ideally suited for the proposed research because of the well-characterized zones of cell growth, proliferation, and differentiation in conjunction with the well-characterized zones of different signaling pathways and cell intrinsic transcriptional factors, and because of the large set of tools that are available in the Drosophila system. Notch signaling is a conserved developmental signaling pathway that has diverse roles in eye development ranging from cell proliferation, differentiation, and cell fate determination. Interestingly, activation of Notch signaling in different regions of the developing retina leads to different outcomes: Notch signaling induces cell growth and proliferation in the anterior of the developing retina but induces differentiation in cells just ahead of the morphogenetic furrow. We hypothesize that the distinct ability of Notch signaling to induce the expression of its targets in different regions of the developing retina is controlled by the interactions between Notch and other signaling pathways or region specific factors, and that the expression of distinct set of targets mediates the different effect of Notch signaling in inducing cell proliferation or differentiation in different regions of the developing retina. To test these hypotheses and to elucidate the mechanisms by which cell proliferation and differentiation is controlled in the developing retina, we have the following three Specific Aims: (1) To investigate the molecular mechanisms by which Notch signaling regulates the cell cycle in the developing retina; (2) To investigate the mechanisms by which the ability of Notch signaling to promote cell growth and proliferation is controlled; (3) To characterize the mechanism by which the initiation of Ato expression is controlled in the Drosophila developing retina. Our long-term objective is to achieve a deep understanding of cell proliferation and differentiation in retinal development, which will potentially lead to the development of new approaches in the prevention, diagnosis, and treatment of retinal diseases as well as other human diseases with cell proliferation or differentiation defect.