Dnmt1 和 Dnmt3a 维持 DNA 甲基化并调节成年大脑前体细胞中的突触功能。
Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.
机构信息
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
出版信息
Nat Neurosci. 2010 Apr;13(4):423-30. doi: 10.1038/nn.2514. Epub 2010 Mar 14.
Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.
Dnmt1 和 Dnmt3a 是重要的 DNA 甲基转移酶，在有丝分裂后神经元中表达，但它们在中枢神经系统中的功能尚不清楚。我们生成了条件性突变小鼠，这些小鼠在大脑皮层兴奋性神经元中特异性缺失 Dnmt1、Dnmt3a 或两者，结果发现只有双敲除（DKO）小鼠的海马 CA1 区表现出异常的长时程可塑性，同时伴有学习和记忆缺陷。尽管我们没有发现神经元丢失，但 DKO 小鼠的海马神经元比野生型小；此外，DKO 神经元的基因表达失调，包括已知有助于突触可塑性的 MHC 类 I 基因和 Stat1。此外，我们观察到 DKO 神经元中的 DNA 甲基化显著减少。我们的结论是，Dnmt1 和 Dnmt3a 通过在维持 DNA 甲基化和调节成年中枢神经系统神经元中的神经元基因表达方面的重叠作用，对于突触可塑性、学习和记忆是必需的。
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