Methyl CpG-binding Protein Isoform MeCP2_e2 Is Dispensable for Rett Syndrome Phenotypes but Essential for Embryo Viability and Placenta Development
Methyl CpG-binding Protein Isoform MeCP2_e2 Is Dispensable for Rett Syndrome Phenotypes but Essential for Embryo Viability and Placenta Development
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DOI：
10.1074/jbc.m111.309864
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发表时间：
2012-04-20
影响因子：
4.8
通讯作者：
Kurimasa, Akihiro
中科院分区：
文献类型：
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作者：
Itoh, Masayuki;Tahimic, Candice G. T.;Kurimasa, Akihiro
甲基CpG结合蛋白2基因（MeCP 2）突变与Rett综合征（RTT）有关，RTT是女性精神发育迟滞的常见原因之一。已经报道了两种MeCP 2亚型：MeCP2_e2（所有四个外显子的剪接）和MeCP2_e1（外显子1、3和4的选择性剪接）。它们的相对表达水平在不同组织中有所不同，MeCP2_e1在成人大脑中更占主导地位，而MeCP2_e2在胎盘、肝脏和骨骼肌中表达更丰富。在这项研究中，我们使用Cre-loxP系统对MeCP2_e2定义的外显子2进行了特异性破坏，并检查了体内MeCP2_e2功能选择性丧失的后果。我们进行了行为评价，基因表达分析，使用RTPCR和实时定量PCR，和组织学分析。我们证明，选择性删除MeCP2_e2不会导致RTT相关的神经系统表型，但赋予一个生存劣势胚胎携带一个MeCP2_e2无效等位基因的母体来源。此外，我们揭示了MeCP2_e2在胚外组织中的功能的特定要求，其中MeCP2_e2的选择性损失导致胎盘缺陷和PEG-1的上调，如由突变等位基因的亲本来源所确定的。总之，我们的研究结果表明，一个新的作用MeCP 2在正常胎盘发育，并说明如何父亲的X染色体失活在胚胎外组织赋予一个突变的母亲MeCP2_e2等位基因的载体的生存劣势。此外，我们的研究结果提供了一个解释，没有报告MeCP2_e2特异性外显子2突变的RTT。人类MeCP2_e2突变可能导致逃避RTT诊断的表型。
Methyl CpG-binding protein 2 gene (MeCP2) mutations are implicated in Rett syndrome (RTT), one of the common causes of female mental retardation. Two MeCP2 isoforms have been reported: MeCP2_e2 (splicing of all four exons) and MeCP2_e1 (alternative splicing of exons 1, 3, and 4). Their relative expression levels vary among tissues, with MeCP2_e1 being more dominant in adult brain, whereas MeCP2_e2 is expressed more abundantly in placenta, liver, and skeletal muscle. In this study, we performed specific disruption of the MeCP2_e2-defining exon 2 using the Cre-loxP system and examined the consequences of selective loss of MeCP2_e2 function in vivo. We performed behavior evaluation, gene expression analysis, using RTPCR and real-time quantitative PCR, and histological analysis. We demonstrate that selective deletion of MeCP2_e2 does not result in RTT-associated neurological phenotypes but confers a survival disadvantage to embryos carrying a MeCP2_e2 null allele of maternal origin. In addition, we reveal a specific requirement for MeCP2_e2 function in extraembryonic tissue, where selective loss of MeCP2_e2 results in placenta defects and up-regulation of peg-1, as determined by the parental origin of the mutant allele. Taken together, our findings suggest a novel role for MeCP2 in normal placenta development and illustrate how paternal X chromosome inactivation in extraembryonic tissues confers a survival disadvantage for carriers of a mutant maternal MeCP2_e2 allele. Moreover, our findings provide an explanation for the absence of reports on MeCP2_e2-specific exon 2 mutations in RTT. MeCP2_e2 mutations in humans may result in a phenotype that evades a diagnosis of RTT.