Mechanisms Underlying Neuronal Enhancer Specification During Postnatal CNS Development

产后中枢神经系统发育过程中神经元增强剂规范的潜在机制

• 批准号: 10578801
• 负责人: MICHAEL ELDON GREENBERG
• 金额: $ 64.96万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578801
• 关键词: Address; Adult; Automobile Driving; Binding; Birth; Brain; Cell Proliferation; Cells; Central Nervous System; Cognition Disorders; Collaborations; Cues; Development; Disease; Distal; Enhancers; Environment; Event; Family; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Enhancer Element; Genetic Transcription; Genome; Genomics; Heterogeneity; Human; Inbred Strains Mice; Individual; Interneurons; Licensing; Life; Mediating; Mediator; Molecular; Nervous System; Neurodevelopmental Disorder; Neurons; Pattern; Physiological; Physiology; Play; Process; Regulator Genes; Regulatory Element; Role; Sensory; Series; Shapes; Specific qualifier value; Stimulus; Technology; Testing; Tissues; Transcription Factor AP-1; Transgenic Organisms; Up-Regulation; Variant; Work; autism spectrum disorder; cell motility; cell type; cognitive function; combat; developmental neurobiology; experience; experimental study; gene repression; genetic approach; insight; mammalian genome; nervous system development; neural; neural circuit; neurodevelopment; neuronal circuitry; postnatal; postnatal development; postnatal period; programs; therapeutic development; transcription factor

The mature central nervous system (CNS) is sculpted by the combined effects of intrinsic genetic programs and dynamic environmental input, yet the precise manner by which these two processes collaborate to give rise to the functional diversity of the mature nervous system remains to be fully explored. Using transgenic approaches that allow for the purification of sparse neuronal subtypes, we find that lineage-committed cortical interneurons undergo dynamic changes in gene expression in the early postnatal period, including the downregulation of genes governing cell proliferation and migration as well as the concomitant upregulation of subtype-specific genes important for mature neuronal function. We recently discovered that this postnatal transition in transcription state is mediated by the licensing and decommissioning of thousands of cis-regulatory enhancer elements across the genome. In the course of defining the regulatory elements that orchestrate these transcriptional changes, we have uncovered a possible role for the AP-1 (Fos/Jun) family of stimulus-inducible transcription factors (TFs) in promoting neuronal maturation through the de novo selection of sets of neuronal subtype-specific enhancer elements, suggesting that external cues from the environment in early life have an instructive role in shaping mature neuronal identities. To gain further insight into the mechanisms mediating early postnatal enhancer selection and its contribution to neural circuit maturation and function, we propose (1) to assess the role of sensory-driven activity in postnatal neuronal enhancer selection, (2) to characterize the molecular mediators of postnatal enhancer selection, and (3) to test the contribution of enhancer remodeling to postnatal neuronal maturation. It is our hope that the proposed experiments will yield a better understanding of the molecular mechanisms underlying enhancer selection in the developing CNS, further illuminate how cell-intrinsic and -extrinsic mechanisms coordinate to drive mature circuit function, and ultimately provide new opportunities for the development of therapeutic strategies to combat a subset of neurodevelopmental disorders.

成熟的中枢神经系统（CNS）是由内在遗传程序和 动态的环境输入，但这两个过程合作产生的确切方式， 成熟神经系统的功能多样性仍有待充分探索。使用转基因方法 允许稀疏神经元亚型的纯化，我们发现谱系定向皮质中间神经元 在出生后早期经历基因表达的动态变化，包括 控制细胞增殖和迁移的基因以及伴随的亚型特异性 对成熟神经元功能重要的基因。我们最近发现，这种出生后的过渡， 转录状态是由数以千计的顺式调节增强子的许可和退役介导的 基因组中的元素。在定义协调这些的监管要素的过程中， 转录变化，我们已经发现了AP-1（Fos/Jun）家族的刺激诱导的可能作用， 转录因子（TF）通过从头选择神经元组来促进神经元成熟 亚型特异性增强子元件，这表明早期生命环境的外部线索具有 在塑造成熟神经元身份方面的指导作用。为了更深入地了解 出生后早期增强子选择及其对神经回路成熟和功能的贡献，我们提出（1） 评估感觉驱动的活动在出生后神经元增强子选择中的作用，（2）表征 出生后增强子选择的分子介质，和（3）测试增强子重塑对 出生后神经元成熟。我们希望，拟议的实验将产生更好的理解， 在发育中的CNS中增强子选择的分子机制，进一步阐明了细胞内在和外在机制如何协调以驱动成熟的电路功能，并最终提供了新的 为开发治疗策略以对抗神经发育障碍的子集提供了机会。