Gene regulation of retinal cell differentiation

视网膜细胞分化的基因调控

• 批准号: 8656122
• 负责人: WEI LIU
• 金额: $ 40.92万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656122
• 关键词: AXIN2 protein; Agonist; Amacrine Cells; Anterior; Binding; Binding Sites; Biological Assay; Cell Differentiation process; Cell Maintenance; Cells; ChIP-seq; Cilia; Commit; Competence; Cone; DNA Binding; Decision Making; Defect; Development; Dissection; Dose; EMSA; Ectopic Expression; Embryo; Enhancers; Event; Eye; Eye Abnormalities; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Generations; Genes; Goals; Homeostasis; Human; In Vitro; Joints; Knowledge; Maintenance; Mediating; Modeling; Molecular; Mus; Nuclear; Outcome; Outcome Study; Pathway interactions; Phenotype; Photoreceptors; Pigment Epithelium; Proliferating; Proteins; Regenerative Medicine; Regulation; Regulatory Pathway; Replacement Therapy; Reporter; Reporter Genes; Research; Retina; Retinal; Retinal Diseases; Retinal Ganglion Cells; Signal Pathway; Signal Transduction; Stem cells; Structure; Structure of retinal pigment epithelium; Transcriptional Regulation; Transgenic Mice; Vision; base; bone morphogenetic protein 4; dehydroretinal; design; genome wide association study; homeodomain; human embryonic stem cell; in vivo; induced pluripotent stem cell; insight; joint function; neural plate; novel; novel strategies; postnatal; public health relevance; research study; retinal neuron; retinal progenitor cell; retinal rods; transcription factor

DESCRIPTION (provided by applicant): Gene regulation of retinal cell differentiation in development is crucial for the generation of mature and functional retinal neurons that form the cellular basis of visual function. Dysregulation in retinal development causes developmental abnormalities of eye and impairs visual function. Stem cell-based regenerative medicine and cell replacement therapy require a better understanding of key developmental regulators and signal pathways in retinal cell differentiation. Our long-term goal of this proposal is to elucidat those molecular mechanisms that control the maintenance of multipotential retinal progenitor cells (RPCs) and their subsequent photoreceptor cell commitment. We predict that RPC-multipotency factors (providing differentiation potentials) and lineage-specific signals act in concert to initiate the expression of decision-making gene(s) that steer(s) a subset of RPCs towards the photoreceptor lineage. However, not much is known about the molecular events in the regulation of RPC multipotency and the initiation of photoreceptor cell differentiation. Homeodomain transcription factors Six3 and Six6 are structurally similar and largely co-expressed in multipotent RPCs in mouse. Our current preliminary studies have identified severe RPC defects in Six3; Six6 compound null retinas; these RPC defects are not evident in either Six3 or Six6 single null retinas. In photoreceptor cell differentiation, homeodomain transcription factor Otx2 is the earliest marker and the essential upstream regulator in a gene network that direct photoreceptor precursors to either rods or cones. Thus, Otx2 is a decision-making gene whose expression marks cell commitment, and dissection of the regulatory components for its neuroretinal expression help unravel as yet unknown molecular mechanisms that promote RPCs to differentiate into photoreceptor precursors. Now we have identified a novel, highly conserved enhancer that recapitulates the initial Otx2 retinal expression. In this proposal we aim 1) to elucidate the regulatory pathways under the control of Six3/Six6 joint functions in retinal cell differentiation and 2) to determine the molecular mechanisms that control Otx2 retinal expression through this Otx2 retinal enhancer. The outcomes of these studies will provide insights into the molecular mechanisms controlling the maintenance of multipotential retinal progenitor cells and photoreceptor cell differentiation, and thus facilitate the design of novel strategies for the generation of specific retinal cells, e.g., photoreceptor cells, from the culturs of human embryonic stem cells or induced pluripotent stem cells in the endeavor of modeling and treatment of human retinal diseases.

描述（由申请人提供）：发育过程中视网膜细胞分化的基因调控对于形成成熟和功能性视网膜神经元至关重要，视网膜神经元构成视觉功能的细胞基础。视网膜发育失调导致眼发育异常，损害视觉功能。基于干细胞的再生医学和细胞替代疗法需要更好地理解视网膜细胞分化的关键发育调节因子和信号通路。我们的长期目标是阐明那些控制维持多潜能视网膜祖细胞（rpc）及其随后的感光细胞承诺的分子机制。我们预测，rpc -多能因子（提供分化潜能）和谱系特异性信号协同作用，启动决策基因的表达，引导rpc子集向光感受器谱系发展。然而，关于RPC多能性调控和光感受器细胞分化起始的分子事件知之甚少。同源结构域转录因子Six3和Six6结构相似，在小鼠多能性rpc中大量共表达。我们目前的初步研究已经确定了Six3的严重RPC缺陷；6个复合无视网膜；这些RPC缺陷在Six3或Six6单个空视网膜中都不明显。在光感受器细胞分化过程中，同源结构域转录因子Otx2是基因网络中最早的标记物，也是引导光感受器前体分化为视杆细胞或视锥细胞的重要上游调控因子。因此，Otx2是一个决策基因，其表达标志着细胞承诺，而对其神经视网膜表达调控成分的解剖有助于揭示促进RPCs分化为光受体前体的未知分子机制。现在我们已经确定了一种新的，高度保守的增强子，它概括了最初的Otx2视网膜表达。在本研究中，我们的目标是：1)阐明Six3/Six6联合功能在视网膜细胞分化中的调控途径；2)确定通过这种Otx2视网膜增强剂控制Otx2视网膜表达的分子机制。这些研究的结果将提供对控制多潜能视网膜祖细胞和光感受器细胞分化维持的分子机制的见解，从而促进从人类胚胎干细胞或诱导多能干细胞培养中产生特定视网膜细胞（如光感受器细胞）的新策略的设计，以努力模拟和治疗人类视网膜疾病。