Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Neuron. 2009 Dec 10;64(5):678-91. doi: 10.1016/j.neuron.2009.11.019.
The genetic basis of cognition and behavioral adaptation to the environment remains poorly understood. Here we demonstrate that the histone methyltransferase complex GLP/G9a controls cognition and adaptive responses in a region-specific fashion in the adult brain. Using conditional mutagenesis in mice, we show that postnatal, neuron-specific deficiency of GLP/G9a leads to derepression of numerous nonneuronal and neuron progenitor genes in adult neurons. This transcriptional alteration is associated with complex behavioral abnormalities, including defects in learning, motivation, and environmental adaptation. The behavioral changes triggered by GLP/G9a deficiency are similar to key symptoms of the human 9q34 mental retardation syndrome that is associated with structural alterations of the GLP/EHMT1 gene. The likely causal role of GLP/G9a in mental retardation in mice and humans suggests a key role for the GLP/G9a-controlled histone H3K9 dimethylation in regulation of brain function through maintenance of the transcriptional homeostasis in adult neurons.
认知和行为适应环境的遗传基础仍知之甚少。在这里，我们证明组蛋白甲基转移酶复合物 GLP/G9a 以特定于区域的方式控制成年大脑中的认知和适应性反应。我们使用小鼠的条件性突变，表明 GLP/G9a 的出生后、神经元特异性缺失导致成年神经元中许多非神经元和神经元祖细胞基因的去抑制。这种转录改变与复杂的行为异常有关，包括学习、动机和环境适应方面的缺陷。GLP/G9a 缺乏引起的行为变化类似于人类 9q34 智力迟钝综合征的关键症状，该综合征与 GLP/EHMT1 基因的结构改变有关。GLP/G9a 在小鼠和人类智力迟钝中的可能因果作用表明，GLP/G9a 控制的组蛋白 H3K9 二甲基化通过维持成年神经元中的转录平衡在调节大脑功能方面起着关键作用。
