Transcriptional regulation of pontine development

脑桥发育的转录调控

• 批准号: 7561023
• 负责人: E DAVID LITWACK
• 金额: $ 32.44万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7561023
• 关键词: Address; Adult; Apoptotic; Biological Models; Brain; Candidate Disease Gene; Cell Death; Cell Nucleus; Cell Survival; Cells; Cerebellum; Cognition; Congenital Abnormality; Data; Defect; Development; Disease; Dose; Embryo; Exhibits; Failure; Family; Family member; Fibrinogen; Gene Expression; Genes; Goals; Individual; Joubert syndrome; Knock-out; Lead; Lip structure; Location; Measures; Modeling; Molecular; Motor; Mus; Mutant Strains Mice; Neurologic; Neurons; Nuclear; Pathway interactions; Phenotype; Play; Pontine structure; Proteins; Regulation; Relative (related person); Research; Role; Specific qualifier value; Staining method; Stains; Stream; System; Testing; Transcriptional Regulation; Western Blotting; cell motility; combinatorial; hindbrain; human NFIA protein; human NFIB protein; human NFIC protein; human NFIX protein; in vivo; insight; member; migration; mutant; nervous system disorder; neurodevelopment; nuclear factor 1; overexpression; progenitor; protein function; research study; therapeutic target; transcription factor

While transcription factors of the Nuclear Factor One (NFI) family are critical for many aspects of neural development, little is known about how they function in vivo. The goal of this research is to determine the mechanisms by which NFI factors direct the development of the basilar pons (BP) and other precerebellar nuclei. These hindbrain nuclei derive from progenitors residing in the rhombic lip,and migrate along unique pathways to their adult locations. Mice lacking the Nfia gene exhibit a moderate reduction in BP size. In Nfib knockouts, however, the BP is virtually absent, with alterations in the pontine migratory stream suggesting defects in both cell survival and cell migration. The respective phenotypes associated with Nfia and Nfib mutant mice imply that NFI-B may play a specific role in directing BP development. Alternatively, NFI factors may be functionally redundant, with overall NFI protein levels being the important determinant of BP development. To test these models of NFI action, experiments in Aim 1 will compare cell death, migration, and specification in both mutants to determine whether Nfia and Nfib regulate BP development by the same mechanisms. Experiments in Aim 2 will determine if other NFI factors can compensate for the loss of Nfib. Expression and rescue studies in Aim 3 will determine if Nfia and Nfib form a regulatory network with Pax6 and other transcription factors to control BP development; this will include the identification of downstream targets of Nfia and Nfib. These studies will address fundamental questions regarding the regulation of neural development by NFI transcription factors and the molecular mechanisms underlying the formation of the precerebellar system. Elucidating these mechanisms is critical for understanding developmental and neurological defects associated with the hindbrain and cerebellum that can lead to severe problems in motor coordination and cognition. Many birth defects and neurological disorders result from the failure of the hindbrain and cerebellum to develop correctly. Studying the molecular mechanisms of hindbrain development will lead to a greater understanding of these disorders, and identify potential therapeutic targets for their treatment.

虽然核因子一 (NFI) 家族的转录因子对于神经系统的许多方面都至关重要。 人们对它们在体内如何发挥作用知之甚少。这项研究的目标是确定 NFI 因素指导基底脑桥 (BP) 和其他小脑前叶发育的机制 原子核。这些后脑核团源自菱形唇部的祖细胞，并沿着独特的方向迁移 通往成年地点的路径。缺乏 Nfia 基因的小鼠表现出血压适度降低。在 然而，Nfib 敲除后，BP 几乎不存在，脑桥迁移流发生改变 表明细胞存活和细胞迁移均存在缺陷。与 Nfia 相关的各自表型 Nfib 突变小鼠表明 NFI-B 可能在指导 BP 发展中发挥特定作用。或者， NFI 因子可能在功能上是多余的，总体 NFI 蛋白水平是重要的决定因素 BP开发。为了测试这些 NFI 作用模型，目标 1 中的实验将比较细胞死亡、 两种突变体的迁移和规范，以确定 Nfia 和 Nfib 是否通过以下方式调节 BP 发展： 相同的机制。目标 2 中的实验将确定其他 NFI 因素是否可以补偿 Nfib 丧失。 Aim 3 中的表达和拯救研究将确定 Nfia 和 Nfib 是否形成监管 与 Pax6 和其他转录因子组成网络来控制 BP 的发展；这将包括 Nfia 和 Nfib 下游靶点的识别。这些研究将解决基本问题 NFI转录因子调控神经发育及其分子机制 是小脑前系统形成的基础。阐明这些机制对于 了解与后脑和小脑相关的发育和神经缺陷 可能导致运动协调和认知方面的严重问题。 许多出生缺陷和神经系统疾病是由于后脑和小脑无法发挥作用造成的。 正确发展。研究后脑发育的分子机制将带来更大的结果 了解这些疾病，并确定其治疗的潜在治疗靶点。