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：
8342204
负责人：
HEINZ ARNHEITER
金额：
$ 84.08万
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

来源：
https://reporter.nih.gov/project-details/8342204
关键词：
Address Adult Biochemical Biological Blindness Bone Morphogenetic Proteins Cell Cycle Cell Lineage Cell Proliferation Cell Therapy Cells Development Developmental Biology Disease Dorsal Epithelium Event Eye Eye Development Fibroblast Growth Factor Future Generations Genetic Goals Helix-Turn-Helix Motifs Homeodomain Proteins Human In Vitro Individual Iris Knowledge Macular degeneration Methods Molecular Monitor Optics Organ Pathogenesis Play Process Regulation Retina Retinal Role Signal Transduction Signaling Molecule Structure of retinal pigment epithelium Time Transcriptional Regulation Transforming Growth Factor beta blastomere structure cell type in vivo induced pluripotent stem cell insight microphthalmia-associated transcription factor monolayer neuroepithelium optic cup optic stalk paralogous gene research study response transcription factor

项目摘要

A critical event in vertebrate eye development is the early separation of the seemingly uniform epithelium of the optic cup into a domain that will become the multilayered retina and a domain that will become the monolayer retinal pigment epithelium or RPE. This separation is controlled by a number of signaling molecules and transcription factors including fibroblast growth factors (FGFs), bone morphogenetic proteins, transforming growth factor-betas, the homeodomain proteins PAX6 and VAX1/2, and the basic helix-loop-helix-zipper protein MITF. One of the early signs of the action of these factors is the establishment of a differential rate of cell proliferation which is high in the future retina and low in the future RPE. This fact prompted us to initiate studies in which we correlate cell cycle parameters with cell signaling and transcription regulation. Interestingly, it appears that peak activities in cell signaling responses may be cell cycle-specific. In separate experiments, we have identified a regulatory loop that involves PAX6, MITF, its paralog TCFEC, and WNT-regulating signaling factors and that is crucial for RPE and retina development. The studies show that PAX6, well-known for its pro-retinogenic activity in the retina, has in fact anti-retinogenic roles in the future RPE, particularly in its dorsal part. Similar roles are played by VAX1/2 in the ventral RPE. A detailed knowledge on the mechanisms regulating early development in vivo may become important for the generation of retinal and RPE cells from embryonic or induced pluripotent stem cells in vitro. Such cells hold much promise for cell-based therapies in human blindness, including adult onset macular degeneration, and for studying the pathogenesis of such diseases at the molecular level. Nevertheless, at the present time, the process of their generation is still not very well controlled and it remains to be seen whether they represent truly authentic cell types. A careful monitoring of the activities of PAX6 and its regulatory partners may therefore become important to efficiently generate functional RPE and retinal cells in vitro.

脊椎动物眼发育中的一个关键事件是，光学杯的看似均匀上皮的早期分离为一个域，该域将成为多层视网膜和一个将成为单层视网膜色素上皮或RPE的域。这种分离受许多信号分子和转录因子的控制，包括成纤维细胞生长因子（FGF），骨形态发生蛋白，转化生长因子 - 贝塔斯，同源构域蛋白PAX6和VAX1/2，以及基本的Helix-loop-helix-Zipper-Zipper-Zipper-Zipper蛋白MITF。这些因素作用的早期迹象之一是建立了细胞增殖的差异速率，这在未来的视网膜中很高，而将来的RPE差异很低。这一事实促使我们启动研究，其中我们将细胞周期参数与细胞信号传导和转录调控相关。有趣的是，看来细胞信号反应中的峰活动可能是细胞周期特异性的。在单独的实验中，我们确定了涉及PAX6，MITF，其旁系同源物TCFEC和WNT调节信号传导因子的调节循环，这对于RPE和RPE和视网膜开发至关重要。研究表明，PAX6以其在视网膜中的促归报活性而闻名，实际上在未来的RPE中具有抗归还作用，尤其是在其背部。 VAX1/2在腹侧RPE中扮演类似的角色。关于调节体内早期发育机制的详细知识对于从胚胎或诱导的多能干细胞的体外产生视网膜和RPE细胞可能变得很重要。这些细胞对人类失明的基于细胞的疗法具有很大的希望，包括成年发作性黄斑变性，并研究了分子水平上此类疾病的发病机理。然而，目前，他们这一代的过程仍然不是很好的控制，还有待观察它们是否代表真正的真实细胞类型。因此，仔细监测PAX6及其调节伙伴的活动可能对在体外有效产生功能性RPE和视网膜细胞可能很重要。