Isoform-specific effects of MeCP2 isoforms on neuronal viability

MeCP2 亚型对神经元活力的亚型特异性影响

• 批准号: 8812928
• 负责人: Santosh R D'Mello
• 金额: $ 18.46万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812928
• 关键词: Isoform; specific; effects; MeCP2; isoforms

DESCRIPTION (provided by applicant): Ever since mutations in the methyl-CpG binding protein 2 (MeCP2) gene were found to be the primary cause of Rett syndrome, there has been a tremendous level of interest in understanding the biology and normal function of MeCP2. The MeCP2 gene is alternatively spliced to generated two isoforms commonly referred to as MeCP2-e1 and MeCP2-e2. The significance of these two isoforms is not known and it is widely believed that there is no functional difference. Indeed, most studies in which MeCP2 is ectopically expressed do not specify which isoforms is being used, and expression studies of MeCP2 rarely distinguish between the two. We find that the two isoforms are differentially regulated in postmitotic neurons that are degenerating. Moreover, the enhanced expression of MeCP2-e2 promotes neuronal death while elevated MeCP2-e1 expression has no such effect. In addition to the differential expression pattern and effect on neuronal viability, the two isofors bind the FoxG1 with dramatically different efficiency. FoxG1 is a transcription factor which promotes neuronal survival and whose mutations have also been linked to Rett syndrome. The specific aims of the proposal are (1) to obtain a more detail understanding of MeCP2-e2-induced neurotoxicity, and (2) to define the relationship between MeCP2 and FoxG1 in the regulation of neuronal survival. Although most studies have focused on the role of MeCP2 during brain development, relatively little is known about its function in postmitotic neurons. Our results suggest that MeCP2 is involved in regulating the survival of postmitotic neurons and that the two isoforms regulate this function differently. Results from our proposed experiments will unravel the relationship between two proteins that are linked to Rett syndrome. Furthermore, they will increase existing knowledge on the regulation of neuronal death by focusing on two proteins whose role in the context of neuronal death has not been adequately studied.

描述（由申请人提供）：自从发现甲基-CpG结合蛋白2（MeCP 2）基因突变是Rett综合征的主要原因以来，人们对了解MeCP 2的生物学和正常功能产生了极大的兴趣。MeCP 2基因选择性剪接产生两种亚型，通常称为MeCP 2-e1和MeCP 2-e2。这两种亚型的意义尚不清楚，人们普遍认为它们没有功能差异。事实上，大多数研究中，MeCP 2异位表达没有具体说明哪种亚型正在使用，和表达研究的MeCP 2很少区分两者。我们发现，这两种亚型的差异调节有丝分裂后的神经元退化。此外，MeCP 2-e2表达增强促进神经元死亡，而MeCP 2-e1表达升高则没有这种作用。除了差异表达模式和对神经元活力的影响外，两种亚型以显著不同的效率结合FoxG 1。FoxG 1是一种促进神经元存活的转录因子，其突变也与Rett综合征有关。该提案的具体目的是（1）获得对MeCP 2-e2诱导的神经毒性的更详细的理解，以及（2）定义MeCP 2和FoxG 1在神经元存活调节中的关系。虽然大多数研究都集中在MeCP 2在大脑发育过程中的作用，但对其在有丝分裂后神经元中的功能知之甚少。我们 结果表明MeCP 2参与调节有丝分裂后神经元的存活，并且两种同种型不同地调节该功能。我们提出的实验结果将揭示与Rett综合征相关的两种蛋白质之间的关系。此外，他们将通过关注两种蛋白质来增加现有的关于神经元死亡调控的知识，这两种蛋白质在神经元死亡的背景下的作用尚未得到充分研究。