Isoform-specific effects of MeCP2 isoforms on neuronal viability

描述(申请人提供)：自从甲基-CpG结合蛋白2(MeCP2)基因突变被发现是Rett综合征的主要原因以来，人们对了解MeCP2的生物学和正常功能产生了极大的兴趣。MeCP2基因被选择性地剪接以产生通常被称为MeCP2-e1和MeCP2-e2的两个亚型。这两种异构体的意义尚不清楚，人们普遍认为这两种亚型没有功能差异。事实上，大多数异位表达MeCP2的研究并没有具体说明使用的是哪种异构体，而对MeCP2的表达研究很少区分这两者。我们发现，这两种异构体在退化的有丝分裂后神经元中受到不同的调节。此外，MeCP2-e2的表达增强促进了神经元的死亡，而MeCP2-e1的表达增强则没有这种作用。除了差异表达模式和对神经元活性的影响外，这两种异构体结合FoxG1的效率也截然不同。FOXG1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)更详细地了解MeCP2-e2诱导的神经毒性，以及(2)明确MeCP2和FoxG1在神经元存活调控中的关系。虽然大多数研究都集中在MeCP2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作用知之甚少。我们的 结果表明，MeCP2参与调节有丝分裂后神经元的存活，并且这两种异构体对这一功能的调节是不同的。我们拟议的实验结果将揭开与Rett综合征有关的两种蛋白质之间的关系。此外，他们将通过专注于两种蛋白质来增加对神经元死亡调控的现有知识，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。

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.