Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice
Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice
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DOI：
10.1073/pnas.0401626101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Jaenisch, R
中科院分区：
文献类型：
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作者：
Luikenhuis, S;Giacometti, E;Jaenisch, R
MECP2基因突变是导致人类Rett综合征（RTT）的原因，Rett综合征是一种主要影响女孩的神经发育障碍。MeCP2是一种结合CpG二核苷酸的蛋白质，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，但在神经胶质中不表达。MeCP2激活的时间与中枢神经系统的成熟有关，最近的报道表明MeCP2可能参与突触接触的形成，并可能在活动依赖性神经元基因表达中发挥作用。小鼠中Mecp2的缺失或靶向突变导致ret样表型。出生后神经元中Mecp2的选择性突变导致类似的表型，尽管延迟，这表明Mecp2在有丝分裂后神经元中起作用。在这里，我们通过将MeCP2表达置于神经元特异性启动子的控制下，验证了RTT症状完全由神经元MeCP2缺陷引起的假设。Mecp2基因在有丝分裂后神经元中的表达导致严重的运动功能障碍症状。然而，在Mecp2突变小鼠中的转基因表达挽救了RTT表型。
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.