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Gene regulation of retinal cell differentiation

视网膜细胞分化的基因调控

基本信息

批准号：
9887357
负责人：
WEI LIU
金额：
$ 41.96万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9887357
关键词：
Adult Affect Amacrine Cells Award Biology Blindness Cell Differentiation process Cell Proliferation Cells Ciliary Body DNA Binding Development Developmental Process FZD1 gene Fibroblast Growth Factor Funding Gene Expression Regulation Genes Genetic Goals Human Individual Iris Knowledge Laboratories Ligands Maintenance Modeling Molecular Morphogenesis Mus Natural regeneration Pathway interactions Pattern Peripheral Phenotype Population Proteins Regenerative Medicine Regulation Research Retina Retinal Degeneration Role Signal Transduction Signal Transduction Pathway Specific qualifier value Stratification Structure Structure of retinal pigment epithelium System Testing Therapeutic Tissues Transforming Growth Factor beta Vision beta catenin cis acting element design differential expression epithelial stem cell genetic corepressor insight mouse model multipotent cell optic cup overexpression paralogous gene postnatal progenitor programs receptor regenerative therapy retinal damage retinal neuron single-cell RNA sequencing stem cells transcription factor transcriptome sequencing

项目摘要

Abstract The long-term goal of this research program is to elucidate the fundamental mechanisms underlying mammalian retinal development through molecularly dissecting the roles of transcription factors and signal transduction molecules. In the adult retina, the neuroretina, retinal pigment epithelium, ciliary body, and iris are structurally connected to execute visual functions. During development, the progenitor cells that give rise to these adult retinal tissues are closely related. Morphogenesis of optic cups results in the specification and regionalization of neuroretinal and retinal pigment epithelial progenitor cells in the inner and outer layers of optic cups, respectively. Subsequently, ciliary margin progenitor cells are specified at the periphery of the neuroretina, contributing to the ciliary body and iris. Neuroretinal progenitor cells are multipotent; their coordinated cell proliferation and differentiation produce stratified neuroretina. Abnormalities in any of developmental processes result in retinal blindness. In retinal development, cell specification, cell identity maintenance, and differentiation are tightly regulated by transcription factors, including Six3, Six6, Pax6, Rax, Sox2, and Lhx2. Signaling transduction pathways, including Wnt, FGF, HH, BMP, and TGFβ, interplay with the transcription factors. How multipotent neuroretinal progenitor cells are regulated, and how the maintenance of neuroretinal progenitor cells and the specification of ciliary margin progenitors are coordinated along the peripheral-central axis are still critical knowledge gaps. In the previous funding period, we have demonstrated that Six3 and Six6 are jointly required for the maintenance of multipotent neuroretinal progenitor cells in mice. We hypothesize that Six3 and Six6 directly regulate multiple major targets to maintain the identity of multipotent neuroretinal progenitor cells. The hypothesis will be tested using both candidate and unbiased approaches. We will first determine the major targets of Six3 and Six6 in suppressing Wnt/β-catenin signaling to maintain multipotent neuroretinal cell identity (Aim 1), and then elucidate the molecular mechanisms by which Six3 and Six6 jointly suppress ciliary margin cell fate at the far periphery but maintain the multipotency of neuroretinal progenitor cells at the mid periphery in the neuroretina (Aim 2). The proposed studies are built upon our intriguing mouse models as well as unbiased cutting-edge approaches already established in our laboratory. When completed, these studies will provide deeper insights into the molecular and cellular mechanisms of retinal differentiation and uncover therapeutic opportunities for regenerative medicine of the human neuroretina. 1

摘要