The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits
The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits
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DOI：
10.1093/hmg/ddn102
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Zhao, Xinyu
中科院分区：
文献类型：
--
作者：
Allan, Andrea M.;Liang, Xiaomin;Zhao, Xinyu
甲基CpG结合蛋白(MBDS)是DNA甲基化介导的表观遗传基因调控的中心成分。表观遗传途径的改变已知与几种神经发育障碍有关，特别是自闭症。我们以前的研究表明，Mbd1基因的缺失导致小鼠海马神经发生减少和学习障碍。然而，MBD1是否调节与自闭症相关的认知功能仍不清楚。在这里，我们显示了Mbd1突变(Mbd1(-/-))小鼠表现出几个经常与自闭症相关的核心缺陷，包括社交减少、学习障碍、焦虑、感觉运动门控缺陷、抑郁和大脑5-羟色胺异常活动。此外，我们发现Mbd1可以通过与其启动子结合来直接调节5-羟色胺受体Htr2c的表达，并且Mbd1的缺失导致Htr2c的表达上调。因此，我们的结果证明了表观遗传调控在哺乳动物大脑发育和认知功能中的重要性。了解Mbd1的缺失如何导致自闭症样的行为表型，将揭示关于自闭症分子发病机制的急需信息。
Methyl-CpG binding proteins (MBDs) are central components of DNA methylation-mediated epigenetic gene regulation. Alterations of epigenetic pathways are known to be associated with several neurodevelopmental disorders, particularly autism. Our previous studies showed that the loss of Mbd1 led to reduced hippocampal neurogenesis and impaired learning in mice. However, whether MBD1 regulates the autism-related cognitive functions remains unknown. Here we show that Mbd1 mutant (Mbd1(-/-)) mice exhibit several core deficits frequently associated with autism, including reduced social interaction, learning deficits, anxiety, defective sensory motor gating, depression and abnormal brain serotonin activity. Furthermore, we find that Mbd1 can directly regulate the expression of Htr2c, one of the serotonin receptors, by binding to its promoter, and the loss of Mbd1 led to elevated expression of Htr2c. Our results, therefore, demonstrate the importance of epigenetic regulation in mammalian brain development and cognitive functions. Understanding how the loss of Mbd1 could lead to autism-like behavioral phenotypes would reveal much-needed information about the molecular pathogenesis of autism.