Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, United States; Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kai Yuan Avenue, Science Park, Guangzhou 510530, China.
Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, United States.
Neurobiol Learn Mem. 2019 Nov;165:106859. doi: 10.1016/j.nlm.2018.04.014. Epub 2018 Apr 24.
Highly expressed in the mammalian brain and widely distributed across the genome, MeCP2 is a key player in recognizing modified DNA and interpreting the epigenetic information encoded in different DNA methylation/hydroxymethylation patterns. Alterations in sequence or copy number of the X-linked human MECP2 gene cause either Rett syndrome (RTT) or MECP2 duplication syndrome. Alterations in MECP2 levels have also been identified in patients with autism. To fully understand the significant role of MECP2 in regulating the development and function of the nervous system, it is important to study all aspects of MeCP2 function. Stimulus-induced MeCP2 phosphorylation has been shown to influence the proliferation and differentiation of neural progenitor cells, synaptic scaling, excitatory synaptogenesis, and animal behavior. However, all of the previous functional evidence is from studying phospho-dead mutations. In addition, the relationship between phosphorylation events at multiple sites on the MeCP2 protein is not well understood. Here, we report the generation of a phospho-mimic knockin Mecp2 mouse line. At the synaptic and behavioral levels, the phospho-mimic Mecp2 mice show phenotypes opposite to those observed in phospho-dead mutation at the same phosphorylation site. Moreover, we report opposite phenotypes between phospho-mutants of two sites on the MeCP2 protein. Our new data further confirm the functional significance of specific MeCP2 phosphorylation event and support the opposing regulatory role between different MeCP2 phosphorylation events.
在哺乳动物大脑中高度表达，并广泛分布于基因组中，MeCP2 是识别修饰 DNA 和解释不同 DNA 甲基化/羟甲基化模式中所编码的表观遗传信息的关键因素。X 连锁人类 MECP2 基因的序列或拷贝数改变会导致雷特综合征（RTT）或 MECP2 重复综合征。自闭症患者的 MECP2 水平也发生了改变。为了充分了解 MECP2 在调节神经系统发育和功能方面的重要作用，研究 MeCP2 功能的各个方面非常重要。刺激诱导的 MeCP2 磷酸化已被证明会影响神经祖细胞的增殖和分化、突触缩放、兴奋性突触发生和动物行为。然而，所有以前的功能证据都来自于研究磷酸化失活突变。此外，MeCP2 蛋白上多个位点的磷酸化事件之间的关系还不是很清楚。在这里，我们报告了一种磷酸模拟敲入 Mecp2 小鼠品系的产生。在突触和行为水平上，磷酸模拟 Mecp2 小鼠表现出与同一磷酸化位点的磷酸化失活突变观察到的表型相反。此外，我们报告了 MeCP2 蛋白上两个位点的磷酸化突变之间的相反表型。我们的新数据进一步证实了特定 MeCP2 磷酸化事件的功能意义，并支持不同 MeCP2 磷酸化事件之间的相反调节作用。
