Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders
Multiple pathways regulate MeCP2 expression in normal brain development and exhibit defects in autism-spectrum disorders
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DOI：
10.1093/hmg/ddh063
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发表时间：
2004-03-15
影响因子：
3.5
通讯作者：
LaSalle, JM
中科院分区：
文献类型：
--
作者：
Samaco, RC;Nagarajan, RP;LaSalle, JM
Rett综合征（RTT）是一种由MECP 2突变引起的神经发育障碍，MECP 2编码甲基CpG结合蛋白2（MeCP 2）。虽然MECP 2是普遍转录，MeCP 2表达是发育调节和异质性的神经元亚群，定义为MeCP 2（lo）和MeCP 2（hi）。为了检验影响MeCP 2表达变化的途径在RTT、自闭症和其他没有MECP 2突变的神经发育障碍中可能有缺陷的假设，在含有来自28名不同的神经发育障碍患者和年龄匹配的对照的额叶皮质样品的组织微阵列上进行MeCP 2表达的高通量定量。通过激光扫描细胞术进行MeCP 2蛋白和多聚腺苷酸化转录物水平的组合定量分析，并测试与年龄匹配的对照组的显著差异。正常大脑样本显示总MeCP 2表达和MeCP 2（hi）细胞百分比随年龄增加，这可以通过MeCP 2（hi）群体内MECP 2转录增加来解释。与胎脑相比，在出生后观察到MeCP 2（lo）群体中长转录本的相对使用显著减少，但交替聚腺苷酸化与单细胞水平的MeCP 2表达变化无关。来自几种相关神经发育障碍的脑样本，包括自闭症、广泛性发育障碍、Prader-Willi和Angelman综合征，通过明显不同的转录和转录后机制，与年龄匹配的对照组相比，MeCP 2表达存在显著差异。这些结果表明，多种途径调节MeCP 2的复杂发育表达，并且除了RTT之外，在自闭症谱系障碍中是有缺陷的。
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG-binding protein 2 (MeCP2). Although MECP2 is ubiquitously transcribed, MeCP2 expression is developmentally regulated and heterogeneous in neuronal subpopulations, defined as MeCP2(lo) and MeCP2(hi). To test the hypothesis that pathways affecting MeCP2 expression changes may be defective in RTT, autism and other neurodevelopmental disorders without MECP2 mutations, a high-throughput quantitation of MeCP2 expression was performed on a tissue microarray containing frontal cortex samples from 28 different patients with neurodevelopmental disorders and age-matched controls. Combined quantitative analyses of MeCP2 protein and alternatively polyadenylated transcript levels were performed by laser scanning cytometry and tested for significant differences from age-matched controls. Normal cerebral samples showed an increase in total MeCP2 expression and the percentage of MeCP2(hi) cells with age that could be explained by increased MECP2 transcription within the MeCP2(hi) population. A significant decrease in the relative usage of the long transcript in the MeCP2(lo) population was observed in postnatal compared to fetal brain, but alternate polyadenylation did not correlate with MeCP2 expression changes at the single cell level. Brain samples from several related neurodevelopmental disorders, including autism, pervasive developmental disorder, Prader-Willi and Angelman syndromes showed significant differences in MeCP2 expression from age-matched controls by apparently different transcriptional and post-transcriptional mechanisms. These results suggest that multiple pathways regulate the complex developmental expression of MeCP2 and are defective in autism-spectrum disorders in addition to RTT.