Tao Jifang, Hu Keping, Chang Qiang, Wu Hao, Sherman Nicholas E, Martinowich Keri, Klose Robert J, Schanen Carolyn, Jaenisch Rudolf, Wang Weidong, Sun Yi Eve
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4882-7. doi: 10.1073/pnas.0811648106. Epub 2009 Feb 18.
Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett syndrome. As a chromatin-associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. Although neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here, we report the identification of several MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors.
MECP2（甲基-CpG结合蛋白2）的突变会导致雷特综合征。作为一种与染色质相关的多功能蛋白，MeCP2如何整合外部信号并调节神经元功能仍不清楚。尽管已有报道称神经元活动可诱导MeCP2在丝氨酸421（S421）处发生磷酸化，但MeCP2磷酸化的全貌以及此类修饰在体内的功能仍有待揭示。在此，我们报告了在多个物种的正常和癫痫大脑中鉴定出多个MeCP2磷酸化位点。我们证明，MeCP2的丝氨酸80（S80）磷酸化至关重要，因为在转基因敲入小鼠中将其突变为丙氨酸（S80A）会导致运动功能缺陷。S80A突变会减弱静息神经元中几个基因启动子处MeCP2与染色质的结合，并导致少数基因的转录变化。神经元中的钙内流会导致S80去磷酸化，这可能有助于其与染色质解离。我们推测，MeCP2的磷酸化调节了其在构成行为基础的神经回路中静息和活跃状态之间转换的神经元中的动态功能。
