State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, University of Chinese Academy of Sciences, Beijing 100049, China, and Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
J Neurosci. 2014 Apr 9;34(15):5184-99. doi: 10.1523/JNEUROSCI.4129-13.2014.
Adult neurogenesis is thought to be crucial for preserving cognitive functions, which is tightly controlled by various epigenetic regulators. As the methyltransferase of histone H3K27, the role of Ezh2 in neurogenesis of adult mice and its mechanism of action are largely unknown. Here, we show that Ezh2 is expressed in actively dividing neural stem cells (NSCs)/progenitor cells as well as mature neurons, but not in quiescent NSCs in the subgranular zone. The deletion of Ezh2 in NSCs/progenitor cells results in a reduction in progenitor cell proliferation. Furthermore, we found that Ezh2 regulates progenitor cell proliferation by suppressing Pten expression and promoting the activation of Akt-mTOR. Moreover, the loss of Ezh2 in progenitor cells leads to a decrease in the number of neurons, which was observed by long-term tracing. Strikingly, conditional knockout of Ezh2 ultimately results in impairments in spatial learning and memory, contextual fear memory, and pattern separation. Our findings demonstrate the essential role of Ezh2 in the proliferation of progenitor cells, thus providing insight into the molecular mechanisms of adult neurogenesis in preserving cognitive functions.
成人神经发生被认为对维持认知功能至关重要，而认知功能受多种表观遗传调节剂的严格控制。作为组蛋白 H3K27 的甲基转移酶，Ezh2 在成年小鼠神经发生中的作用及其作用机制在很大程度上尚不清楚。在这里，我们表明 Ezh2 在活跃分裂的神经干细胞（NSC）/祖细胞以及成熟神经元中表达，但不在颗粒下区的静止 NSC 中表达。NSC/祖细胞中 Ezh2 的缺失导致祖细胞增殖减少。此外，我们发现 Ezh2 通过抑制 Pten 表达和促进 Akt-mTOR 的激活来调节祖细胞增殖。此外，祖细胞中 Ezh2 的缺失导致神经元数量减少，这可以通过长期示踪观察到。引人注目的是，Ezh2 的条件性缺失最终导致空间学习和记忆、情境恐惧记忆和模式分离受损。我们的研究结果表明 Ezh2 在祖细胞增殖中的重要作用，从而为成年神经发生在维持认知功能中的分子机制提供了深入了解。
