Function of math5 in Retinal Development

描述（由申请人提供）：本提案的长期目标 是了解脊椎动物视网膜发育的分子机制， 以确定调节视网膜神经元正常分化的基因。 在小鼠中，math 5和brn-3b在发育中的视网膜中早期表达。 分别从胚胎第11天和第11.5天（E11和E11.5）开始。他们的 视网膜中的时间和空间表达模式与 视网膜神经节细胞（RGC）分化，表明它们在视网膜神经节细胞分化中的作用。 RGCs的分化。以前的研究表明， 小鼠中brn-3b的缺失导致轴突形成的失败， 视网膜发育早期RGCs的程序性细胞死亡。目标 math 5的突变导致大量RGC的缺失， brn-3b在视网膜发育过程中RGC特异性表达。的表达和 突变研究表明，数学5是前神经基因的 视网膜前体细胞中RGCs的发育和math 5的表达 决定了视网膜神经节细胞的命运此外，brn-3b的缺失 在math 5-null视网膜中的表达表明brn-3b是math 5-null视网膜的下游。 RGC发育中math 5调控通路的效应基因。三 提出了具体的目标，以精确地定义math 5在视网膜中的作用。 math 5与brn-3b的关系：（1）小鼠 将创建细胞系以激活lacZ报告基因的稳定表达 在表达math 5的细胞中， 在整个发展中。具体而言，math 5突变对RGC的影响 分化、迁移、程序性细胞死亡或转化为非RGC 命运将被评估。(2)math 5将视网膜神经元 将通过在视网膜祖细胞中表达math 5来测试将视网膜祖细胞转化为RGC 细胞或视网膜外植体培养物中。(3)监管关系 将使用math 5和brn-3b突变体分析brn-3b和math 5之间的差异 小鼠和常规启动子分析方法。获得的信息 这些研究将大大促进我们对 正常视网膜发育中的转录因子和视网膜发育中的转录因子 退化性疾病这些研究的结果可以提供基础， 设计维持视网膜细胞活力的治疗方法， 再生视网膜神经元。

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.