Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains
Methyl CpG-binding protein 2 (a mutation of which causes Rett syndrome) directly regulates insulin-like growth factor binding protein 3 in mouse and human brains
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DOI：
10.1097/nen.0b013e3180302078
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发表时间：
2007-02-01
影响因子：
3.2
通讯作者：
Goto, Yu-ichi
中科院分区：
文献类型：
--
作者：
Itoh, Masayuki;Ide, Shuhei;Goto, Yu-ichi
Rett综合征（RTT）是一种主要的神经发育障碍，以智力低下和自闭症行为为特征。编码甲基CpG结合蛋白2的MeCP2基因突变导致该疾病。MeCP2功能障碍导致RTT表型的病理机制尚未阐明。我们发现MeCP2直接调节人和小鼠脑中胰岛素样生长因子结合蛋白3（IGFBP3）基因的表达。染色质免疫沉淀分析表明IGFBP3启动子含有MeCP2结合位点。使用实时定量聚合酶链反应和蛋白质印迹分析，在mecp2缺失小鼠和人RTT患者的脑中观察到IGFBP3过表达。此外，mecp2基因敲除小鼠在大脑皮层中显示出广泛分布和数量增加的IGFBP3阳性细胞，而相同年龄的野生型小鼠显示出较少的IGFBP3阳性细胞。这些结果表明，IGFBP3是一个下游基因的调节MeCP 2和以前报道的BDNF和DLX5基因和MeCP 2可能直接有助于IGFBP3在大脑中的转录表达。有趣的是，mecp2基因敲除小鼠的病理特征与IGFBP3转基因小鼠的病理特征有一些相似之处，后者显示出出生后早期生长的减少。由于缺乏MeCP2而导致的IGFBP3过表达可能导致脑成熟延迟。
Rett syndrome (RTT) is a major neurodevelopmental disorder, characterized by mental retardation and autistic behavior. Mutation of the MeCP2 gene, encoding methyl CpG-binding protein 2, causes the disease. The pathomechanisin by which MeCP2 dysfunction leads to the RTT phenotype has not been elucidated. We found that MeCP2 directly regulates expression of insulin-like growth factor binding protein 3 (IGFBP3) gene in human and mouse brains. A chromatin immunoprecipitation assay showed that the IGFBP3 promoter contained an MeCP2 binding site. IGFBP3 overexpression was observed in the brains of mecp2-null mice and human RTT patients using real-time quantitative polymerase chain reaction and Western blot analyses. Moreover, mecp2-null mice showed a widely distributed and increased number of IGFBP3-positive cells in the cerebral cortex, whereas wild-type mice at the same age showed fewer IGFBP3-positive cells. These results suggest that IGFBP3 is a downstream gene regulated by MeCP2 and that the previously reported BDNF and DLX5 genes and MeCP2 may contribute directly to the transcriptional expression of IGFBP3 in the brain. Interestingly, the pathologic features of mecp2-null mice have some similarities to those of IGFBP3-transgenic mice, which show a reduction of early postnatal growth. IGFBP3 overexpression due to lack of MeCP2 may lead to delayed brain maturation.