Function of math5 in Retinal Development

math5在视网膜发育中的作用

• 批准号: 6754471
• 负责人: Lin Gan
• 金额: $ 35.89万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754471
• 关键词: apoptosis; cell differentiation; cell migration; cytogenetics; developmental genetics; gel mobility shift assay; gene expression; gene mutation; gene targeting; laboratory mouse; neurons; organ culture; retinal ganglion; transcription factor

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to understand the molecular mechanisms of vertebrate retinal development and to identify the genes regulating the normal differentiation of retinal neurons. In mice, math5 and brn-3b are expressed early in the developing retinas starting at embryonic day 11 and 11.5 (E11 and E 11.5), respectively. Their temporal and spatial expression pattern in retina correlates with the onset of retinal ganglion cell (RGC) differentiation, suggesting their roles in the differentiation of RGCs. Previous studies have demonstrated that targeted deletion of brn-3b in mice causes the failure of axon formation and the programmed cell death of RGCs in early retinal development. The targeted mutation of math5 results in the absence of a large set of RGCs and abolishes the RGC-specific expression of brn-3b in developing retina. The expression and mutation studies have suggested that math 5 is the proneural gene for the development of RGCs and expression of math5 in the retinal progenitor cells defines the retinal ganglion cell fate. In addition, the absence of brn-3b expression in math5-null retinas suggests that brn-3b is the downstream effector gene of the math5 regulatory pathway in RGC development. Three specific aims are proposed to precisely define the role of math5 in retinal development and to establish relationship between math5 and brn-3b: (1) Mouse lines will be created to activate the stable expression of lacZ reporter gene in math5-expressing cells and the fates of these cells will be analyzed throughout development. Specifically, the effect of math5 mutation on RGC differentiation, migration, programmed cell death or converting to non-RGC fates will be assessed. (2) The ability of math5 to convert the retinal progenitors into RGCs will be tested by expressing math5 in retinal progenitor cells in vivo or in retina explant cultures. (3) The regulatory relationship between brn-3b and math5 will be analyzed using the math5 and brn-3b mutant mice and conventional promoter analysis approaches. Information obtained from these studies will significantly advance our understanding of the roles of transcriptional factors in normal retinal development and in retinal degenerative diseases. Results of these studies could provide the foundation of designing therapeutic approaches to maintain retinal cell viability and to regenerate retinal neurons.

描述（由申请人提供）：该提案的长期目标 是了解脊椎动物视网膜发育的分子机制 鉴定调节视网膜神经元正常分化的基因。 在小鼠中，math5 和 brn-3b 在视网膜发育早期表达 分别从胚胎第 11 天和 11.5 天（E11 和 E 11.5）开始。他们的 视网膜的时间和空间表达模式与发病相关 视网膜神经节细胞（RGC）分化，表明它们在 RGC 的分化。先前的研究表明，有针对性的 小鼠中 brn-3b 的缺失会导致轴突形成失败 早期视网膜发育过程中 RGC 的程序性细胞死亡。所针对的 math5 的突变导致缺乏大量 RGC 并废除 brn-3b 在视网膜发育中的 RGC 特异性表达。表达式和 突变研究表明 math 5 是 视网膜祖细胞中 RGC 的发育和 math5 的表达 定义视网膜神经节细胞的命运。此外，brn-3b的缺失 math5-null 视网膜中的表达表明 brn-3b 是下游 RGC 发育中 math5 调控途径的效应基因。三 提出了具体目标来精确定义 math5 在视网膜中的作用 开发并建立 math5 和 brn-3b 之间的关系： (1) 鼠标 将创建细胞系以激活 lacZ 报告基因的稳定表达 在表达 math5 的细胞中，这些细胞的命运将被分析 整个开发过程中。具体来说，math5突变对RGC的影响 分化、迁移、程序性细胞死亡或转化为非 RGC 命运将受到评估。 (2) math5转换视网膜的能力 将通过在视网膜祖细胞中表达 math5 来测试 RGC 的祖细胞 体内或视网膜外植体培养物中的细胞。 （三）监管关系 brn-3b 和 math5 之间的差异将使用 math5 和 brn-3b 突变体进行分析 小鼠和常规启动子分析方法。获得的信息来自 这些研究将极大地增进我们对以下角色的理解： 正常视网膜发育和视网膜中的转录因子 退行性疾病。这些研究的结果可以提供基础 设计治疗方法以维持视网膜细胞活力并 再生视网膜神经元。