Genetic Control of Retina Specification

描述（由申请人提供）：为视网膜疾病的预防、诊断和治疗创造新的工具需要对视网膜细胞命运决定和分化的分子机制有更多的了解。这种竞争性更新的目标是确定高度保守的哺乳动物Dach基因在视网膜发育和成人中的功能。小鼠和人类都有两个同源的果蝇基因达克斯猎犬，编码一种新的转录辅助因子，这对果蝇的视网膜发育既必要又充分。dachshund的小鼠同源物，命名为Dach1和Dach2，在胚胎和出生后的视网膜中表达。此外，Dach1的表达依赖于Math5， Math5编码一种dna结合转录因子，这是神经节细胞规范所必需的。我们假设Dach基因是视网膜正常发育所必需的。虽然Dach1零突变体在出生时死亡，没有明显的视网膜表型，但由于新生儿的致死率，在发育过程中无法进行分析。因此，Dach1可能在眼睛发育过程中起晚期作用，或者与Dach2存在功能冗余。为了进一步探索这种可能性并帮助阐明视网膜细胞命运控制的分子机制，我们将使用Cre/loxP系统创建这两个基因的条件等位基因。我们提出以下具体目标：

DESCRIPTION (provided by applicant): Generating new tools for the prevention, diagnosis, and treatment of retinal diseases requires an increased understanding of the molecular mechanisms of retinal cell fate determination and differentiation. The goal of this competing renewal is to determine the function of the highly conserved mammalian Dach genes during retinal development and in adults. Both mice and humans possess two homologs of the Drosophila gene dachshund, which encodes a novel transcriptional cofactor that is both necessary and sufficient for retinal development in Drosophila. Mouse homologs of dachshund, named Dach1 and Dach2, are expressed in the retina during embryonic and postnatal life. In addition, Dach1 expression is dependent upon Math5, which encodes a DNA-binding transcription factor that is required for ganglion cell specification. We hypothesize that the Dach genes are required for normal retinal development. Although Dach1 null mutants die at birth with no obvious retinal phenotype, analysis later during development is precluded by neonatal lethality. Thus Dach1 may play a late role during eye development or there may be functional redundancy with Dach2. To further explore this possibility and to help elucidate the molecular mechanisms of retinal cell fate control, we will create conditional alleles of both genes using the Cre/loxP system. We propose the following Specific Aims: 1. Analyze Dach1 function during postnatal retinal development.2. Determine the role of Dach2 function during embryonic and postnatal retinal development.3. Place Dach1 and Dach2 in a retinal hierarchy with Pax6, Math5, and Brn3b. These studies are required to characterize the relationships between genes operating during retinal development. A greater understanding of these pathways is essential to our understanding of eye disease. Since our approach focuses on vertebrate homologues of the Drosophila gene dachshund, which is both necessary and sufficient for eye development, it is likely that uncovering the similarities and differences in retinal specification pathways is a key to the future development of diagnostic and therapeutic tools.