Analysis of a novel regulator of vertebrate retinal neurogenesis

脊椎动物视网膜神经发生的新型调节剂的分析

• 批准号: 7295668
• 负责人: Monica L Vetter
• 金额: $ 14.95万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7295668
• 关键词: Alleles; Animal Model; BHLH Protein; Cell Cycle; Cell Cycle Regulation; Cell Differentiation process; Cell Nucleus; Cell membrane; Cells; Class; Co-Immunoprecipitations; Degenerative Disorder; Depth; Development; Disease; Ectoderm; Eye Abnormalities; Gene Targeting; Genes; Genetic; Genetic Transcription; Goals; Helix-Turn-Helix Motifs; Localized; Maps; Membrane; Mitotic; Molecular; Mus; Mutant Strains Mice; Mutation; Nervous system structure; Neural Retina; Neuronal Differentiation; Nuclear; Numbers; Orthologous Gene; Pathway interactions; Pattern; Play; Population; Process; Proliferating; Protein Overexpression; Protein Region; Proteins; Research Personnel; Retina; Retinal; Retinal Degeneration; Retinal Ganglion Cells; Role; Signal Pathway; Signaling Protein; Staging; Testing; Time; Translations; Work; Xenopus; Yeasts; cell type; deletion analysis; gene function; genetic analysis; in vivo; insight; intracellular protein transport; loss of function; mutant; neural plate; neurogenesis; notch protein; novel; progenitor; programs; protein localization location; relating to nervous system; research study; retinal neuron; retinal progenitor cell; stem; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): A number of congenital eye disorders stem from alterations in early development, including proliferation and differentiation of progenitors within the neural retina, although in many cases the mechanisms underlying these disorders is not understood. By defining the mechanisms controlling normal retinal neurogenesis, we may gain a better understanding of how these processes are disrupted in pathological situations. bHLH transcription factors play a pivotal role in retinal neurogenesis, but remarkably little is known about how they control the process of retinal neuron differentiation. We have identified a new gene, sbt1, which encodes a novel protein that is expressed in the developing Xenopus nervous system and which is regulated by proneural bHLH activity. Our preliminary results indicate that sbt1 is an essential regulator of retinal neurogenesis in Xenopus. We have identified a mouse ortholog of this gene, and showed that it is also expressed in the nervous system and has a conserved ability to regulate retinal neuron differentiation. Here we propose to develop two new directions for the analysis of sbt1 function. In Specific Aim 1 we will initiate a study of sbt1 during mouse retinal development by performing a detailed analysis of sbt1 expression, and determining whether its expression depends upon proneural bHLH factors. In Specific Aim 2 we will analyze subcellular localization of sbt1 and define protein partners for this novel protein. The experiments in this proposal will provide the conceptual framework for an in-depth genetic study of sbt1, a novel and exciting gene that appears to be a key regulator of neuronal differentiation in the developing retina. A long-term hope is that we may ultimately be able to manipulate the differentiation of retinal stem cells or progenitors to treat retinal degenerative diseases. Our work will contribute to this effort by characterizing the molecular mechanisms underlying retinal neuron differentiation and cell fate specification.

描述(申请人提供)：许多先天性眼病源于早期发育的改变，包括神经视网膜内祖细胞的增殖和分化，尽管在许多情况下，这些疾病的潜在机制尚不清楚。通过定义控制正常视网膜神经发生的机制，我们可能会更好地理解这些过程在病理情况下是如何被破坏的。BHLH转录因子在视网膜神经发生中起着关键作用，但人们对它们如何控制视网膜神经元分化过程知之甚少。我们已经发现了一个新的基因sbt1，它编码一种新的蛋白，该蛋白在非洲爪哇发育的神经系统中表达，并受原神经bHLH活性的调节。我们的初步结果表明，sbt1是非洲爪哇视网膜神经发生的重要调节因子。我们已经确定了该基因的一个小鼠同源基因，并表明它也在神经系统中表达，并具有调节视网膜神经元分化的保守能力。在这里，我们提出了两个新的方向来分析sbt1函数。在特定的目标1中，我们将通过对sbt1的表达进行详细的分析，并确定其表达是否依赖于神经bHLH因子，从而启动对sbt1在小鼠视网膜发育过程中的研究。在特定的目标2中，我们将分析sbt1的亚细胞定位，并确定这种新蛋白的蛋白质伙伴。这项提议中的实验将为深入研究sbt1的遗传学提供概念框架，sbt1是一种新的令人兴奋的基因，似乎是发育中的视网膜神经元分化的关键调节因子。一个长期的希望是，我们最终可能能够操纵视网膜干细胞或祖细胞的分化来治疗视网膜退行性疾病。我们的工作将通过表征视网膜神经元分化和细胞命运指定的分子机制来为这一努力做出贡献。