Mechanisms underlying neuronal enhancer specification during postnatal CNS development

出生后中枢神经系统发育过程中神经元增强子规范的潜在机制

基本信息

批准号：
10360618
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
项目类别：
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/10360618
关键词：
Address Adult Automobile Driving Binding Birth Brain Cell Proliferation Cells Cognition Disorders Cues Development Disease Distal Down-Regulation 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 Instruction Interneurons Licensing Life Mediating Mediator of activation protein Molecular Nervous system structure Neuraxis Neurodevelopmental Disorder Neurons Pattern Physiological Physiology Play Process Regulator Genes Regulatory Element Role Sensory Series Shapes Specific qualifier value Stimulus Technology Testing Tissues To specify 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 genetic approach insight mammalian genome nervous system development neural circuit neurodevelopment postnatal postnatal development postnatal period programs relating to nervous system therapeutic development transcription factor

项目摘要

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环境输入，但这两个过程协作产生的精确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纯化稀疏神经元亚型，我们发现谱系定向的皮质中间神经元在出生后早期经历基因表达的动态变化，包括下调控制细胞增殖和迁移以及亚型特异性的伴随上调的基因对成熟神经元功能很重要的基因。我们最近发现这种产后转变转录状态由数千个顺式调节增强子的许可和停用介导整个基因组的元素。在定义协调这些的监管要素的过程中转录变化，我们发现了刺激诱导型 AP-1 (Fos/Jun) 家族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，表明生命早期环境的外部线索具有在塑造成熟神经元身份方面具有指导作用。为了进一步了解调解机制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，以及（3）测试增强子重塑的贡献出生后神经元成熟。我们希望所提出的实验能够更好地理解发育中的中枢神经系统中增强子选择的分子机制，进一步阐明细胞内在和外在机制如何协调以驱动成熟的电路功能，并最终提供新的开发治疗策略来对抗一部分神经发育障碍的机会。