Role of Microphthalmia/MITF Factor in Eye Development

小眼症/MITF 因子在眼睛发育中的作用

• 批准号: 8128476
• 负责人: FRANCESCA PIGNONI
• 金额: $ 33.91万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8128476
• 关键词: Age related macular degeneration; Area; Biological Models; Cell membrane; Cellular Morphology; Defect; Development; Disease; Dominant-Negative Mutation; Drosophila genus; Employee Strikes; Epithelial; Epithelium; Eye; Eye Development; Eye diseases; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Grant; Head; Hearing; Homologous Gene; Hybrids; Knowledge; Lead; Life; Link; Membrane; Microphthalmos; Molecular; Morphology; Mus; Mutation; One-Step dentin bonding system; Optic vesicle; Pathway interactions; Pattern; Phenotype; Photoreceptors; Pigment Epithelium of Eye; Pigmentation physiologic function; Play; Proliferating; Protein Binding; Proteins; Retina; Retinal; Role; Stem cells; Structure; Structure of retinal pigment epithelium; Tissue Differentiation; Tissues; Two-Hybrid System Techniques; Vertebrates; Yeasts; bone; eye formation; fly; gain of function; in vitro Assay; in vivo; loss of function; molecular marker; mutant; neurogenesis; progenitor; protein function; transcription factor

DESCRIPTION (provided by applicant): In the mouse, the Microphthalmia-related Transcription Factor (Mitf) plays a critical role in the development of the retinal pigmented epithelium (RPE) of the eye. Mitf is one of the determinants of RPE identity and contributes to the proliferation, specification and differentiation of this tissue. In the fly, dMitf \s expressed within the eye disc (the progenitor tissue that gives rise to the retina and surrounding head structures). Interestingly, it is expressed in the peripodial membrane (PM) a region of the disc epithelium that, similarly to the presumptive RPE region of the optic vesicle/cup, (a) does not itself form retina, (b) is juxtaposed to and continuous with the retinal epithelium, and (c) transiently expresses the fly homologues of two other transcription factors (Pax6 and Otx2) known to function in RPE formation. As shown here, dMitf controls proliferation in the eye disc can suppress retinal identity and may contribute to the specification of the non-neural portion of the epithelium. These striking similarities strongly suggest that RPE and PM cells are evolutionarily related and that a conserved Mitf genetic pathway functions during RPE and PM development. For these reasons, we propose to investigate the function(s) of dMitf during eye development in the Drosophila model system. The specific aims proposed in this grant focus on two main areas: The analysis of dMitf function in eye disc development and the identification of additional components of the pathway. Through the detailed loss-of-function and gain-of-function studies proposed in the first two aims, we will establish how dMitf contributes to specification/differentiation of the PM and normal proliferation of the eye disc. In the last two aims and as a first step towards characterizing the dMitf pathway, we propose to identify additional components through yeast 2-hybrid and genetic-interaction screens. We believe that these approaches will lead to the identification of additional conserved factors that function with Mitf during eye formation in fly and vertebrates. Mutations in the mouse Mitf locus cause microphthalmia, pigmentation, bone and hearing defects and the RPE promotes proper survival and function of photoreceptor cells throughout life as well as influences retinal neurogenesis and lamination during development. These critical roles of the RPE in eye formation and function are highlighted by the significant number of diseases associated with genes specifically expressed or enriched in the RPE as well as by the link between RPE dysfunction and several eye diseases including age-related macular degeneration (AMD).

描述（由申请人提供）：在小鼠中，小眼相关转录因子（Mitf）在眼睛视网膜色素上皮（RPE）的发育中起着关键作用。 Mitf 是 RPE 特性的决定因素之一，有助于该组织的增殖、规范和分化。在果蝇中，dMitf 在眼盘（产生视网膜和周围头部结构的祖组织）内表达。有趣的是，它在视盘上皮的足周膜（PM）区域中表达，与视神经泡/视杯的假定 RPE 区域类似，（a）本身不形成视网膜，（b）与视网膜上皮并列并连续，（c）瞬时表达已知在视网膜中起作用的两种其他转录因子（Pax6和Otx2）的果蝇同源物。 RPE 形成。如此处所示，dMitf 控制眼盘中的增殖，可以抑制视网膜特性，并可能有助于上皮非神经部分的规范。这些惊人的相似性强烈表明 RPE 和 PM 细胞在进化上相关，并且保守的 Mitf 遗传途径在 RPE 和 PM 发育过程中发挥作用。由于这些原因，我们建议研究 dMitf 在果蝇模型系统眼睛发育过程中的功能。 本次资助提出的具体目标集中在两个主要领域：分析眼盘发育中的 dMitf 功能以及识别该通路的其他组成部分。通过前两个目标中提出的详细功能丧失和功能获得研究，我们将确定 dMitf 如何促进 PM 的规范/分化和眼盘的正常增殖。在最后两个目标中，作为表征 dMitf 途径的第一步，我们建议通过酵母 2 杂交和遗传相互作用筛选来鉴定其他成分。我们相信，这些方法将导致鉴定出在果蝇和脊椎动物眼睛形成过程中与 Mitf 一起发挥作用的其他保守因子。 小鼠 Mitf 基因座的突变会导致小眼症、色素沉着、骨骼和听力缺陷，而 RPE 会促进感光细胞在整个生命过程中的正常存活和功能，并影响发育过程中的视网膜神经发生和分层。 RPE 在眼睛形成和功能中的这些关键作用通过大量与 RPE 中特异性表达或富集的基因相关的疾病以及 RPE 功能障碍与包括年龄相关性黄斑变性 (AMD) 在内的多种眼部疾病之间的联系来凸显。