Chen Wen G, Chang Qiang, Lin Yingxi, Meissner Alexander, West Anne E, Griffith Eric C, Jaenisch Rudolf, Greenberg Michael E
Division of Neuroscience, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Science. 2003 Oct 31;302(5646):885-9. doi: 10.1126/science.1086446.
Mutations in MeCP2, which encodes a protein that has been proposed to function as a global transcriptional repressor, are the cause of Rett syndrome (RT T), an X-linked progressive neurological disorder. Although the selective inactivation of MeCP2 in neurons is sufficient to confer a Rett-like phenotype in mice, the specific functions of MeCP2 in postmitotic neurons are not known. We find that MeCP2 binds selectively to BDNF promoter III and functions to repress expression of the BDNF gene. Membrane depolarization triggers the calcium-dependent phosphorylation and release of MeCP2 from BDNF promoter III, thereby facilitating transcription. These studies indicate that MeCP2 plays a key role in the control of neuronal activity-dependent gene regulation and suggest that the deregulation of this process may underlie the pathology of RT T.
甲基化CpG结合蛋白2（MeCP2）发生突变会导致瑞特综合征（RTT），这是一种X连锁的进行性神经疾病。MeCP2编码一种被认为具有全局转录抑制功能的蛋白质。尽管在神经元中选择性失活MeCP2足以在小鼠中产生类似瑞特综合征的表型，但MeCP2在有丝分裂后神经元中的具体功能尚不清楚。我们发现，MeCP2选择性地与脑源性神经营养因子（BDNF）启动子III结合，并抑制BDNF基因的表达。膜去极化触发钙依赖性磷酸化，并使MeCP2从BDNF启动子III上释放，从而促进转录。这些研究表明，MeCP2在神经元活动依赖性基因调控中起关键作用，并提示这一过程的失调可能是RTT发病机制的基础。
