Transcription Regulation In Vertebrate Eye Development

脊椎动物眼睛发育中的转录调控

• 批准号: 7969537
• 负责人: HEINZ ARNHEITER
• 金额: $ 82.16万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969537
• 关键词: Address; Alleles; Back; Biochemical; Biological; Brain; Candidate Disease Gene; Cell Lineage; Cells; Cornea; Development; Developmental Biology; Disease; Dorsal; Eye; Eye Development; Gene Expression; Gene Expression Profiling; Gene Targeting; Generations; Genes; Genetic; Goals; Individual; Iris; Lead; Mediating; Melanins; Methods; Molecular; Mus; Mutation; Optics; Organ; Photoreceptors; Pigments; Play; Process; Proteins; Regulation; Repression; Retina; Role; Structure; Structure of retinal pigment epithelium; Transcriptional Regulation; Vertebrates; homeodomain; insight; lens; neuroepithelium; optic stalk; overexpression; transcription factor

All eyes show an association of photoreceptors with dark pigment. In vertebrates, this association can be traced back to the actions of the bHLH-Zip transcription factor MITF, which controls the generation of melanin-bearing pigment cells, and the paired-domain transcription factor PAX6, which controls the generation of photoreceptors in the retina. High level expression of these transcription factors is usually mutually exclusive, except in the neuroepithelium-derived retinal pigment epithelium (RPE) where MITF and PAX6 are co-expressed during development. We approached the question of the role of PAX6 in the RPE genetically, using a variety of mouse Mitf and Pax6 alleles individually and in combinations. The results show that a reduction in the level of functional PAX6 protein exacerbates the dorsal RPE-to-retina transition normally associated with Mitf mutations, and that overexpression of PAX6 protein alleviates this Mitf-mediated RPE-to-retina transition. In fact, candidate gene expression analyses and gene expression profiling indicate that in the RPE, Pax6 normally reduces the expression of pro-retinogenic genes, while in the retina, it promotes their expression. Given that Pax6 plays important roles in the development of cornea, lens, retina and now RPE, we conclude that it is involved in the development of all major structures of the vertebrate eye. Its expression, however, does not extend towards the developing eyes' connection to the brain, called the optic stalk, where its expression is in part suppressed by the homeodomain transcription factors VAX1/2. However, the combination of mutations in Vax1 and Vax2 does not only lead to a de-repression of Pax6 but also a de-repression of Mitf and, consequently, a conversion of the dorsal optic stalk into an RPE. Hence, during eye development, PAX6, MITF, and VAX1/2 are crucial to set up the correct boundaries between retina and RPE and between RPE and optic stalk. Current studies aimed at understanding the set of target genes activated by the respective transcription factors will eventually give us insights into abnormal eye development and disease.

所有的眼睛都表现出感光体与深色色素的关联。在脊椎动物中，可以追溯到控制黑色素含有色素细胞的产生的BHLH-ZIP转录因子MITF的作用，以及配对的域转录因子PAX6，该因子控制了视网膜中光感受器的产生。这些转录因子的高水平表达通常是相互排斥的，除了在神经上皮衍生的视网膜色素上皮（RPE）中，其中MITF和PAX6在发育过程中共表达。我们使用各种小鼠MITF和PAX6等位基因单独和组合处理了PAX6在RPE遗传上的作用的问题。结果表明，功能性PAX6蛋白水平的降低加剧了通常与MITF突变相关的背部RPE-RPE-RETINA转变，并且PAX6蛋白的过表达减轻了MITF介导的RPE-RPE-RPE-RPE转换。实际上，候选基因表达分析和基因表达谱分析表明，在RPE中，PAX6通常会降低促返回基因的表达，而在视网膜中，它促进了它们的表达。鉴于PAX6在角膜，镜头，视网膜和现在的RPE的发展中起着重要作用，我们得出结论，它参与了脊椎动物眼的所有主要结构的发展。然而，它的表达并没有延伸到发育中的眼睛与大脑的联系，称为视茎，其中它的表达部分被同源域转录因子vax1/2抑制。但是，VAX1和VAX2中突变的组合不仅会导致PAX6的抑制，而且会导致MITF的抑制，因此，背侧视觉茎的转化为RPE。因此，在眼睛发育过程中，PAX6，MITF和VAX1/2对于在视网膜和RPE之间以及RPE和Optic Stalk之间建立正确的边界至关重要。目前的研究旨在理解各自转录因子激活的靶基因集，最终将使我们对眼睛发育异常和疾病的见解。