Luikenhuis Sandra, Giacometti Emanuela, Beard Caroline F, Jaenisch Rudolf
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA.
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6033-8. doi: 10.1073/pnas.0401626101. Epub 2004 Apr 6.
Mutations in MECP2 are the cause of Rett syndrome (RTT) in humans, a neurodevelopmental disorder that affects mainly girls. MeCP2 is a protein that binds CpG dinucleotides and is thought to act as a global transcriptional repressor. It is highly expressed in neurons, but not in glia, of the postnatal brain. The timing of MeCP2 activation correlates with the maturation of the central nervous system, and recent reports suggest that MeCP2 may be involved in the formation of synaptic contacts and may function in activity-dependent neuronal gene expression. Deletion or targeted mutation of Mecp2 in mice leads to a Rett-like phenotype. Selective mutation of Mecp2 in postnatal neurons leads to a similar, although delayed, phenotype, suggesting that MeCP2 plays a role in postmitotic neurons. Here we test the hypothesis that the symptoms of RTT are exclusively caused by a neuronal MeCP2 deficiency by placing Mecp2 expression under the control of a neuron-specific promoter. Expression of the Mecp2 transgene in postmitotic neurons resulted in symptoms of severe motor dysfunction. Transgene expression in Mecp2 mutant mice, however, rescued the RTT phenotype.
MECP2基因的突变是人类雷特综合征（RTT）的病因，这是一种主要影响女孩的神经发育障碍。MeCP2是一种与CpG二核苷酸结合的蛋白质，被认为是一种全局转录抑制因子。它在出生后大脑的神经元中高度表达，但在胶质细胞中不表达。MeCP2激活的时间与中枢神经系统的成熟相关，最近的报道表明MeCP2可能参与突触接触的形成，并可能在依赖活动的神经元基因表达中发挥作用。小鼠中Mecp2的缺失或靶向突变会导致类似雷特综合征的表型。出生后神经元中Mecp2的选择性突变会导致类似但延迟出现的表型，这表明MeCP2在有丝分裂后神经元中发挥作用。在这里，我们通过将Mecp2的表达置于神经元特异性启动子的控制之下，来检验雷特综合征症状完全由神经元MeCP2缺乏引起这一假设。有丝分裂后神经元中Mecp2转基因的表达导致严重运动功能障碍的症状。然而，Mecp2突变小鼠中的转基因表达挽救了雷特综合征的表型。
