DNA methylation in Neuronal and Glial Differentiation

神经元和神经胶质分化中的 DNA 甲基化

• 批准号: 6893361
• 负责人: Guoping Fan
• 金额: $ 35.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893361
• 关键词: DNA methylation; apoptosis; biological models; cell differentiation; cell proliferation; electrophysiology; gene expression; genetically modified animals; glia; hippocampus; laboratory mouse; mutant; nerve stem cell; neurogenesis; neurogenetics; neurons; p53 gene /protein; synapses; terminal nick end labeling

DESCRIPTION (provided by applicant): DNA methylation is a major epigenetic factor involved in gene regulation, genomic imprinting, and X-chromosome inactivation. Aberrant DNA methylation has been associated with several human mental retardation disorders including Rett, ICF, Fragile-X, and ATRX syndromes. However, little is known about how DNA methylation changes perturb neural function and lead to neurological disorders. The long-term objective of our research is to elucidate the role of DNA methylation in neural development and function. Using the conditional gene knockout approach, we have recently constructed a strain of mutant mice in which the maintenance methyltransferase gene Dnmtl is deleted exclusively in precursor cells of the central nervous system (CNS). Dnmtl deficiency in CNS precursor cells causes significant demethylation in differentiating neurons and glial cells. Mutant embryos carrying 95 percent of hypomethylated CNS cells die immediately after birth, indicating that hypomethylation disrupts vital CNS function for animal survival. In mosaic animals carrying 30 percent of Dnmtl-/- cells in the embryonic CNS, mutant cells are selectively eliminated during postnatal maturation, showing that methylation is also important for the survival of postnatal CNS cells. The goal of this proposal is to characterize the neural defects in the hypomethylated brain and define the molecular mechanism by which DNA hypomethylation influences the survival and differentiation of neurons and glia. Our working hypothesis is that DNA hypomethylation results in inappropriate expression of many neural genes, which subsequently leads to multiple defects during CNS development. We therefore propose the following Specific Aims: 1. To determine the effect of DNA hypomethylation on the cell fate determination of CNS precursor cells. 2. To determine whether DNA hypomethylation affects neuronal maturation and synaptic function. 3. To define the mechanism of cell death triggered by DNA hypomethylation in the postnatal CNS environment. The proposed study may provide fundamental insights into the role of DNA methylation in neural development as well as the disease mechanism underlying certain mental retardation disorders.

描述(由申请人提供)：DNA甲基化是参与基因调控、基因组印记和X染色体失活的主要表观遗传因素。DNA甲基化异常与几种人类精神发育迟滞疾病有关，包括Rett、ICF、Fragile-X和ATRX综合征。然而，人们对DNA甲基化如何改变神经功能并导致神经疾病知之甚少。我们研究的长期目标是阐明DNA甲基化在神经发育和功能中的作用。利用条件性基因敲除方法，我们最近构建了一种突变小鼠，其中维持甲基转移酶基因Dnmt1在中枢神经系统(CNS)的前体细胞中完全缺失。中枢神经系统前体细胞DNMTL缺乏导致分化中神经元和神经胶质细胞的显著去甲基化。携带95%低甲基化CNS细胞的突变胚胎在出生后立即死亡，这表明低甲基化扰乱了动物生存所必需的CNS功能。在胚胎CNS中携带30%DNMTL-/-细胞的镶嵌动物中，突变细胞在出生后成熟过程中被选择性地消除，表明甲基化对出生后CNS细胞的生存也是重要的。该建议的目的是描述低甲基化大脑中的神经缺陷，并确定DNA低甲基化影响神经元和神经胶质细胞存活和分化的分子机制。我们的工作假设是DNA低甲基化导致许多神经基因的不适当表达，从而导致中枢神经系统发育过程中的多个缺陷。因此，我们提出了以下具体目标：1.确定DNA低甲基化对中枢神经系统前体细胞命运决定的影响。2.探讨DNA低甲基化对神经元成熟和突触功能的影响。3.明确DNA低甲基化在出生后中枢神经系统环境中引发细胞死亡的机制。这项拟议的研究可能会为DNA甲基化在神经发育中的作用以及某些精神发育迟滞障碍的疾病机制提供基本的见解。