Characterization of ME1 during neuronal differentiation

神经元分化过程中 ME1 的表征

• 批准号: 9727443
• 负责人: Anne Chiaramello
• 金额: $ 27万
• 依托单位: George Washington University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=9727443&HistoricalAwards=false
• 关键词: Characterization; ME1; during; neuronal; differentiation

9727443 CHIARAMELLO The general focus of this project is on the mechanisms that govern mammalian neuronal differentiation. Dr. Chiaramello will investigate the roles of the basic helix-loop- helix transcription factor ME1 during brain development. The ME1 gene encodes two isoforms of ME1, called ME1a and ME1b, due to alternative splicing of the messenger RNA. However, only the ME1a form is neuron-specific. Several lines of evidence suggest that ME1 plays an important role in the development of the nervous system: 1) It has a strong homology with transcription factors known to be essential for cell determination and differentiation in the nervous system, such as Drosophila gene Daughterless; 2) It is expressed in areas of the nervous system where neuronal differentiation and plasticity occur; 3) It is also detected in the subependymal region of the adult brain which includes constitutively proliferating cells (neural progenitor cells) as well as relatively quiescent cells that have the capacity to self- renew and give rise to neurons and glia; 4) It modulates the expression of two neuronal target genes involved in neuronal growth and development, GAP-43 and the low affinity nerve growth factor receptor p75LNGFR; and 5) It can assume distinct functions as a transcription factor, acting either as an activator or repressor. In this application, we propose experiments to further investigate ME1 with respect to its molecular mechanism of action and its neuron-specific partners during neuronal differentiation. The specific aims of this project are as follows: In specific aim I, Dr. Chiaramello will examine the posttranslational modification of ME1a during neuronal differentiation by assessing whether phosphorylation of ME1a by casein kinase II dictates the transcriptional activities of ME1 on neuronal target genes. In specific Aim II, Dr. Chiaramello will unravel the molecular mechanism of action of ME1a during neuronal differentiation. ME1a binds DNA as eit her a homodimer or heterodimer. The specificity of the genes regulated by ME1 are thought to depend on the dimerization partner. Therefore, it is of tremendous importance to identify the heterodimeric partners of ME1a. In specific Aim III, Dr. Chiaramello will analyze in detail the temporal and spatial expression of novel partners identified in Aim II. Results from the project will elucidate the cascade of regulatory events necessary for neuronal differentiation.

9727443 Chiaramello 该项目的主要重点是哺乳动物神经元分化的机制。 Chiaramello博士将研究基本螺旋-环-螺旋转录因子ME 1在大脑发育过程中的作用。 由于信使RNA的选择性剪接，ME 1基因编码ME 1的两种亚型，称为ME 1a和ME 1b。 然而，只有ME 1a形式是神经元特异性的。 有证据表明ME 1在神经系统的发育中起重要作用：1）它与已知的神经系统中细胞决定和分化所必需的转录因子（如果蝇基因Daughterless）具有很强的同源性; 2）它在神经系统中发生神经元分化和可塑性的区域表达; 3）在成人脑的室管膜下区域也检测到它，该区域包括组成性增殖细胞。（神经祖细胞）以及具有自我更新能力并产生神经元和神经胶质的相对静止的细胞; 4）它调节参与神经元生长和发育的两个神经元靶基因GAP-43和低亲和力神经生长因子受体p75 LNGFR的表达;和5）它可以作为转录因子承担不同的功能，作为激活因子或阻遏因子。 在此应用中，我们提出的实验，以进一步研究ME 1的分子机制的行动和它的神经元特异性合作伙伴在神经元分化。 该项目的具体目标如下：在具体目标I中，Chiaramello博士将通过评估酪蛋白激酶II对ME 1a的磷酸化是否决定ME 1对神经元靶基因的转录活性，来研究ME 1a在神经元分化过程中的翻译后修饰。 在具体目标II中，Chiaramello博士将揭示ME 1a在神经元分化过程中的分子作用机制。 ME 1a以同源二聚体或异源二聚体的形式结合DNA。 由ME 1调节的基因的特异性被认为取决于二聚化伴侣。 因此，鉴定ME 1a的异二聚体伴侣是非常重要的。 在具体的目标III中，Chiaramello博士将详细分析目标II中确定的新伙伴的时间和空间表达。 该项目的结果将阐明神经元分化所需的级联调节事件。