NMDA REGULATES HOMEOBOX GENE EXPRESSION IN NEURONS

NMDA 调节神经元中的同源框基因表达

• 批准号: 3416681
• 负责人: ROBERT F BULLEIT
• 金额: $ 11.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3416681
• 关键词: DNA binding protein; NMDA receptors; RNA; brain cell; cell differentiation; cell growth regulation; cell migration; cell type; cerebellar Purkinje cell; cerebellum; complementary DNA; gene expression; genetic regulation; genetic regulatory element; genetic transcription; glia; granule; homeobox genes; in situ hybridization; laboratory mouse; molecular cloning; neurogenesis; neurons; northern blottings; nucleic acid sequence; phenotype; polymerase chain reaction; tissue /cell culture; transcription factor

The mammalian brain is composed of a large and diverse number of neuronal phenotypes. These phenotypes are specified during CNS development by a complex interplay of cellular and molecular events. In humans, perturbations in this complex development of brain neurons may lead to deficits in CNS function associated with mental retardation or other neurologic disorders. At present we have only a minimal understanding of the cellular and molecular mechanisms thal regulate this specification of mammalian neuronal phenotypes. The identification of these mechanisms will be important in gaining a better understanding of CNS development. A neuron's phenotype is ultimately determined by the array of genes expressed within that particular cell and by the proteins that regulate transcription from these genes. The homeobox genes encode one class of proteins likely to play a role in determining a neuron's phenotype. These proteins appear to be transcriptional regulatory factors which are required for specification of cellular phenotypes. We are presently using recombinant DNA methodologies to identify homeobox genes expressed in mouse cerebellar granule neurons. A primary focus of our work is to study the expression of these homeobox genes in developing granule neurons. We are particularly interested in identifying molecular mechanisms responsible for regulating their expression. This regulation is likely to be critical for the specification of the granule neuron phenotype. Recent studies, evaluating CNS cell linages, have suggested that some CNS neuron phenotypes are determined by local interactions occurring after the last cell division. These interactions may occur as synaptic connections are made between developing neurons and their' targets. It is possible that these interaction involve neurotransmitters released from target neurons. We are presently evaluating whether neurotransmitters can modulate homeobox gene expression in developing cerebellar granule neurons in vitro. Preliminary data suggests that the level of transcripts encoding at least one homeobox gene is increased in response to the neurotransmitter glutamate. This modulation appears to be via activation of N-methyl-D-aspartate (NMDA) receptors. These studies will be extended to provide a more detailed characterization of the response of these cell to NMDA, including an evaluation of whether this modulation in RNA level is a result of changes in transcript synthesis.

哺乳动物的大脑由大量不同数量的神经元组成 表型。 这些表型是在中枢神经系统发育过程中由 细胞和分子事件的复杂相互作用。 在人类中， 大脑神经元复杂发育的扰动可能会导致 与智力低下或其他相关的中枢神经系统功能缺陷 神经系统疾病。 目前我们对此只有最低限度的了解 调节这种规范的细胞和分子机制 哺乳动物神经元表型。 这些机制的识别将 对于更好地了解中枢神经系统的发育具有重要意义。 神经元的表型最终由基因阵列决定 在该特定细胞内表达并由调节的蛋白质表达 这些基因的转录。 同源盒基因编码一类 蛋白质可能在决定神经元的表型中发挥作用。 这些 蛋白质似乎是所需的转录调节因子 用于细胞表型的规范。 我们目前正在使用 鉴定小鼠中表达的同源框基因的重组 DNA 方法 小脑颗粒神经元。 我们工作的一个主要重点是研究 这些同源框基因在发育中的颗粒神经元中的表达。 我们是 对确定负责的分子机制特别感兴趣 调节他们的表达。 这项规定可能对于 颗粒神经元表型的规范。 最近的研究， 评估中枢神经系统细胞谱系，表明一些中枢神经系统神经元表型 由最后一个单元之后发生的局部相互作用决定 分配。 这些相互作用可能在突触连接建立时发生 发育中的神经元与其目标之间的关系。 有可能这些 相互作用涉及从目标神经元释放的神经递质。 我们是 目前正在评估神经递质是否可以调节同源盒基因 在体外发育的小脑颗粒神经元中的表达。 初步的 数据表明编码至少一个同源框的转录本水平 基因因神经递质谷氨酸的反应而增加。 这 调节似乎是通过激活 N-甲基-D-天冬氨酸 (NMDA) 受体。 这些研究将得到扩展，以提供更详细的信息 这些细胞对 NMDA 反应的特征，包括 评估 RNA 水平的这种调节是否是变化的结果 在转录合成中。