Transcription Regulation In Vertebrate Eye Development

脊椎动物眼睛发育中的转录调控

基本信息

批准号：
7735262
负责人：
HEINZ ARNHEITER
金额：
$ 83.82万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

All eyes show an association of photoreceptors with dark pigment. In vertebrates, this association can be traced back to the action 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 they 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 from a yeast artificial chromosome transgene alleviates this Mitf-mediated RPE-to-retina transition. Hence, the results suggest that in the RPE, Pax6 has an anti-retinogenic role, in contrast to its pro-retinogenic role in the retina. To address the question of the molecular pathways involved in this anti-retinogenic activity of Pax6, we use a candidate gene approach, employing RT-PCR to obtain temporal and spatial gene expression data at the mRNA level and immunocytochemistry to obtain corresponding data at the protein level. Moreover, we use chromatin immunoprecipitation procedures on dissected embryonic eye tissues to establish transcription factor interactions with the regulatory regions of potential target genes. These studies should help us to determine the molecular mechanisms of RPE versus retina development and give insights into the evolutionarily conserved use of Mitf and Pax6 and its homologs in eye development from jellyfish to man.

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，在发育过程中它们共表达。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，并且从酵母菌染色体转基因中过表达Pax6蛋白会缓解这种MITF介导的RPE介导的RPE-RPE-RETINA介导的RPE-RPE-RETINA TRUSITITION。因此，结果表明，在RPE中，PAX6具有抗归还作用，与其在视网膜中的促返回作用相反。为了解决PAX6这种抗归还活性的分子途径的问题，我们使用候选基因方法，采用RT-PCR在mRNA水平上获得时间和空间基因表达数据，并在蛋白质水平上获得相应的数据。此外，我们在解剖的胚胎眼组织上使用染色质免疫沉淀程序来建立与潜在靶基因调节区域的转录因子相互作用。这些研究应帮助我们确定RPE与视网膜发育的分子机制，并深入了解MITF和PAX6的进化保守使用及其在眼睛发育中从水母到人的眼睛发育中的同源物。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mammalian paramutation: a tail's tale?

DOI：
10.1111/j.1600-0749.2006.00351.x
发表时间：
2007-02-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
0
作者：
Arnheiter, Heinz
通讯作者：
Arnheiter, Heinz

Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity.

DOI：
10.1371/journal.pone.0001639
发表时间：
2008-02-20
期刊：
PloS one
影响因子：
3.7
作者：
Lee JY;Muenzberg H;Gavrilova O;Reed JA;Berryman D;Villanueva EC;Louis GW;Leinninger GM;Bertuzzi S;Seeley RJ;Robinson GW;Myers MG;Hennighausen L
通讯作者：
Hennighausen L

When pigment cells turn into neurons.

当色素细胞变成神经元时。