FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice
FXYD1 is an MeCP2 target gene overexpressed in the brains of Rett syndrome patients and Mecp2-null mice
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DOI：
10.1093/hmg/ddm007
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发表时间：
2007-03-15
影响因子：
3.5
通讯作者：
Ojeda, Sergio R.
中科院分区：
文献类型：
--
作者：
Deng, Vivianne;Matagne, Valerie;Ojeda, Sergio R.
Rett综合征（RTT）是一种与MECP2基因杂合新生突变相关的x连锁神经发育障碍。MECP2编码甲基CpG结合蛋白2 (MECP2)，其通过与对称定位的CpG二核苷酸上的5-甲基胞嘧啶残基结合来抑制基因转录。RTT发病机制的直接MeCP2靶点在很大程度上仍然未知。在这里，我们报道FXYD1编码Na+，K+- atp酶活性的跨膜调节剂，在RTT患者和mecp2缺失小鼠的额叶皮质（FC）神经元中升高。增加神经元FXDY1表达足以减少树突状树突和脊柱形成，这是RTT神经病理学的标志。mecp2缺失小鼠皮质神经元Na+、K+- atp酶活性降低，提示FXYD1异常表达导致RTT神经元活动异常。MeCP2通过与FC神经元中甲基化的Fxyd1启动子序列直接相互作用来抑制Fxyd1的转录。因此，FXYD1是MeCP2的靶基因，其去抑制可能直接参与RTT神经元的发病机制。
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to heterozygous de novo mutations in the MECP2 gene. MECP2 encodes methyl-CpG-binding protein 2 (MeCP2), which represses gene transcription by binding to 5-methylcytosine residues in symmetrically positioned CpG dinucleotides. Direct MeCP2 targets underlying RTT pathogenesis remain largely unknown. Here, we report that FXYD1, which encodes a transmembrane modulator of Na+,K+-ATPase activity, is elevated in frontal cortex (FC) neurons of RTT patients and Mecp2-null mice. Increasing neuronal FXDY1 expression is sufficient to reduce dendritic arborization and spine formation, hallmarks of RTT neuropathology. Mecp2-null mouse cortical neurons have diminished Na+,K+-ATPase activity, suggesting that aberrant FXYD1 expression contributes to abnormal neuronal activity in RTT. MeCP2 represses Fxyd1 transcription through direct interactions with sequences in the Fxyd1 promoter that are methylated in FC neurons. FXYD1 is therefore a MeCP2 target gene whose de-repression may directly contribute to RTT neuronal pathogenesis.