Coordination of Gene Expression in Retinal Development

视网膜发育中基因表达的协调

• 批准号: 6923116
• 负责人: KENNETH PATRICK MITTON
• 金额: $ 28.3万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6923116
• 关键词: binding proteins; biological signal transduction; developmental genetics; developmental neurobiology; gene expression; gene induction /repression; gene mutation; histogenesis; laboratory mouse; receptor expression; retina; rhodopsin; transcription factor; visual photoreceptor

DESCRIPTION (provided by applicant): Throughout development, and in the mature retina, precise control of gene expression is essential for photoreceptor integrity and function. This includes control of time, place and level of expression. Transcription factors provide the activation and repression inputs that control gene expression in response to signaling pathways. While much progress has been made towards our understanding of transcriptional activators, our knowledge of the repressors that contribute to the precise regulation of rod-specific genes remains sparse. This proposal will study the role of a novel repressor (Fiz1) that was discovered, by the P.I., from its association with an essential activator (NRL) of rod differentiation and rod-specific gene expression. Stringent regulation of the rhodopsin gene offers a useful paradigm of rod-specific gene expression to explore the interactions between activators, repressors, and signaling pathways. Several transcription factors (NRL. NR2E3. CRX) are shown to be activators of rhodopsin expression. Mutations in these transcription factors cause retinal degeneration. Fiz1 is a zinc-finger protein that was discovered binding to NRL, and behaves as a transcriptional repressor of the rhodopsin gene promoter. Recent studies in the P.l.'s laboratory have shown that Fiz1 protein levels rise in the retina with the onset of rod-specific gene expression. Fiz1 also binds to NR2E3, another transcription factor that is essential for rod development. Fiz1 is detected throughout the cell and can interact with the intracellular domain of a membrane receptor tyrosine-kinase (Flt-3). Levels of the extracellular protein (Flt-3-Ligand, FL) that activates this receptor, also rise during rod-maturation. We hypothesize that Fiz1 is a transcriptional repressor of rod-specific genes and is required for generating quantitatively precise levels of expression in response to extracellular signals. Furthermore, we suggest that Fiz1 assists in the recruitment of proteins that regulate physical access of the transcriptional machinery to DNA. The specific aims of this proposal are: 1. Determine the expression patterns of Fiz1, Flt-3 and FL during retinal development. 2. Identify Fiz1-binding proteins from the retina. 3. Examine the effect of Fiz1 gain and loss of function mutations on mouse rod-photoreceptor development. These aims will elucidate the physiological role of Fiz1 in rod-photoreceptors, and discover additional components of rod-specific transcriptional regulatory networks.

描述（由申请人提供）：在整个开发中，在成熟的视网膜中，基因表达的精确控制对于光感受器的完整性和功能至关重要。这包括对时间，位置和表达水平的控制。转录因子提供了响应信号通路的基因表达的激活和抑制输入。尽管我们对转录激活剂的理解已经取得了很大的进步，但我们对有助于精确调节杆特异性基因的阻遏物的了解仍然很少。该建议将研究由P.I.与杆分化和杆特异性基因表达的必需激活剂（NRL）相关的新型阻遏物（FIZ1）的作用。 对视紫红质基因的严格调节提供了杆特异性基因表达的有用范式，以探索激活剂，阻遏物和信号通路之间的相互作用。几种转录因子（NRL。NR2E3。CRX）被证明是视紫红质表达的激活剂。这些转录因子的突变导致视网膜变性。 FIZ1是一种发现与NRL结合的锌指蛋白，并且表现为视紫红质基因启动子的转录阻遏物。 P.L.实验室的最新研究表明，随着杆特异性基因表达的发作，视网膜中FIZ1蛋白水平上升。 FIZ1还与NR2E3结合，NR2E3是对ROD发育至关重要的另一种转录因子。在整个细胞中检测到FIZ1，并可以与膜受体酪氨酸激酶（FLT-3）的细胞内结构域相互作用。激活该受体的细胞外蛋白水平（FLT-3-ligand，fl，fl），在杆成熟过程中也升高。我们假设FIZ1是杆特异性基因的转录阻遏物，是响应细胞外信号的定量精确表达水平所必需的。此外，我们建议FIZ1有助于募集调节转录机械对DNA的物理获取的蛋白质。该提案的具体目的是： 1。确定视网膜发育过程中FIZ1，FLT-3和FL的表达模式。 2。从视网膜中识别fiz1结合蛋白。 3。检查FIZ1增益和功能突变损失对小鼠杆杆受体发育的影响。 这些目的将阐明FIZ1在杆状受体中的生理作用，并发现杆特异性转录调节网络的其他组件。