Temporal Regulation of Neuronal Differentiation

神经元分化的时间调节

• 批准号: 8097943
• 负责人: DANIEL L KILPATRICK
• 金额: $ 31.74万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097943
• 关键词: Address; Binding; Biological Assay; Cell Separation; Central Nervous System Diseases; Cerebellar Nuclei; Cerebellum; Chromatin; Chromatin Structure; Code; Complex; Defect; Development; Disease; Distal; Dominant-Negative Mutation; Elements; Ensure; Event; Family; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Health; Histone Deacetylase; Individual; Knockout Mice; Link; Longitudinal Studies; Mutation; Nervous system structure; Neuronal Differentiation; Neurons; Pattern; Phase; Process; Protein Family; Proteins; Regulation; Relative (related person); Repression; Role; Staging; Time; Trans-Activators; Transcriptional Regulation; Transgenic Organisms; base; chromatin modification; in vivo; inhibitor/antagonist; insight; knockout gene; nervous system development; nervous system disorder; neuron development; postnatal; programs; promoter; transcription factor

DESCRIPTION (provided by applicant): Neuronal development requires the unfoldment of a highly complex differentiation program. Deciphering the regulatory code underlying this program has direct relevance for CNS disease, since many disorders arise from disruption of one or more neuronal differentiation events. In particular, it is now clear that the interplay between transcription factors and dynamic changes in chromatin structure during neuronal development is altered in several nervous system disorders. As neurons mature, they pass through successive maturation stages in which unique subsets of genes must be turned on and off in the proper sequence and timing. Altering this temporal program can result in serious developmental defects. Individual transcription factors often function during multiple stages of neuronal differentiation, and what determines the temporal patterning for the distinct subsets of genes they control at different steps is not understood. The central goal of this proposal is to define the critical timekeeping mechanisms that ensure the sequential ordering of gene transcription during neuronal differentiation. To address this, we are exploring the temporal regulation of a neuron-specific gene during development. In this proposal, we will examine key interactions between trans-activators, trans-repressors and chromatin structure that collaborate in determining the regulation of the transcriptional timer involved. We will examine temporal interactions of different trans-factors and chromatin modifiers with native chromatin as well as various chromatin modifications occurring within the target gene locus, both in primary neurons and within the CNS. Promoter analyses also will be performed in primary neuronal cultures and in vivo using transgenic approaches. In addition, specific gene knockouts for candidate timekeepers will be examined to determine whether trans-factor disruption alters the transcriptional timer in vivo. Results from these studies will provide insight into how different phases of neuronal development are coordinated to ensure appropriate maturation and function. They also will identify important developmental regulators that may underlie CNS disorders. PUBLIC HEALTH RELEVANCE Defects in genes that control the proper formation of the nervous system frequently giver is to severe neurological disorders. Our studies will identify key mechanisms that determine the appropriate timing of nervous system development as well as candidate CNS disease-related genes involved in this process.

描述（由申请人提供）：神经元发育需要展开高度复杂的分化程序。 破译该程序背后的监管代码与中枢神经系统疾病直接相关，因为许多疾病是由一种或多种神经元分化事件的破坏引起的。 特别是，现在很清楚，在神经元发育过程中转录因子和染色质结构动态变化之间的相互作用在几种神经系统疾病中发生了改变。 随着神经元的成熟，它们会经历连续的成熟阶段，其中必须以正确的顺序和时间打开和关闭独特的基因子集。 改变这个时间程序可能会导致严重的发育缺陷。 单个转录因子通常在神经元分化的多个阶段发挥作用，并且是什么决定了它们在不同步骤控制的不同基因子集的时间模式尚不清楚。 该提案的中心目标是定义关键的计时机制，以确保神经元分化期间基因转录的顺序。 为了解决这个问题，我们正在探索神经元特异性基因在发育过程中的时间调控。 在本提案中，我们将研究反式激活因子、反式抑制因子和染色质结构之间的关键相互作用，这些相互作用共同决定所涉及的转录计时器的调节。 我们将检查不同反式因子和染色质修饰剂与天然染色质的时间相互作用，以及初级神经元和中枢神经系统内靶基因位点内发生的各种染色质修饰。 还将使用转基因方法在原代神经元培养物和体内进行启动子分析。 此外，还将检查候选计时器的特定基因敲除，以确定反式因子破坏是否会改变体内的转录计时器。 这些研究的结果将深入了解神经元发育的不同阶段如何协调以确保适当的成熟和功能。 他们还将确定可能导致中枢神经系统疾病的重要发育调节因子。 公共卫生相关性 控制神经系统正常形成的基因缺陷经常导致严重的神经系统疾病。 我们的研究将确定决定神经系统发育适当时机的关键机制以及参与该过程的候选中枢神经系统疾病相关基因。

项目成果

Reciprocal autoregulation by NFI occupancy and ETV1 promotes the developmental expression of dendrite-synapse genes in cerebellar granule neurons.

• DOI: 10.1091/mbc.e15-07-0476
• 发表时间: 2016-05-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Ding B;Cave JW;Dobner PR;Mullikin-Kilpatrick D;Bartzokis M;Zhu H;Chow CW;Gronostajski RM;Kilpatrick DL
• 通讯作者: Kilpatrick DL

Temporal regulation of nuclear factor one occupancy by calcineurin/NFAT governs a voltage-sensitive developmental switch in late maturing neurons.

• DOI: 10.1523/jneurosci.3533-12.2013
• 发表时间: 2013-02-13
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Ding B;Wang W;Selvakumar T;Xi HS;Zhu H;Chow CW;Horton JD;Gronostajski RM;Kilpatrick DL
• 通讯作者: Kilpatrick DL

BDNF activates an NFI-dependent neurodevelopmental timing program by sequestering NFATc4.

• DOI: 10.1091/mbc.e16-08-0595
• 发表时间: 2018-04-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Ding B;Dobner PR;Mullikin-Kilpatrick D;Wang W;Zhu H;Chow CW;Cave JW;Gronostajski RM;Kilpatrick DL
• 通讯作者: Kilpatrick DL

Gene expression in maturing neurons: regulatory mechanisms and related neurodevelopmental disorders.

• 发表时间: 2015-04
• 期刊: Sheng li xue bao : [Acta physiologica Sinica]
• 作者: Baojin Ding