The Role of MeCP2 in Rett Syndrome

描述（由申请人提供）：Rett综合征（RTT）是一种x连锁神经发育障碍，由编码甲基CpG结合蛋白2 （MECP2）的MECP2突变引起。RTT是唯一已知遗传原因的自闭症谱系障碍，在其他自闭症谱系神经发育障碍中也观察到MECP2突变或表达缺陷。因此，研究MECP2在大脑发育中的作用与智力低下和自闭症具有广泛的相关性。自1999年发现MECP2突变是RTT的遗传原因以来，对MECP2功能的理解不断发展。虽然MeCP2被预测为甲基化基因的全局转录抑制因子，但MeCP2仅在出生后大脑发育过程中被需要，此时表达水平升高。为了使未来的实验更精确地关注缺乏的MeCP2在RTT发病机制中的作用，我们提出了MeCP2作为一种动态的神经元核因子，通过改变亚核定位来调节参与神经元成熟的基因的新模型。本实验旨在验证MECP2/ MECP2外显子2的选择性剪接和翻译后修饰在神经元成熟过程中调控亚核定位和差异蛋白关联的假设。目的1将确定MeCP2e1和MeCP2e2亚型之间亚核定位和蛋白质关联的差异。目的2将研究MeCP2靶基因的核蛋白关联和亚核定位的变化。目的3将通过全基因组染色质免疫沉淀方法确定MeCP2的新靶点，并将测试每个靶基因与RTT发病机制的相关性。这些结果有望在理解RTT的分子发病机制方面具有重要意义，并将有助于设计未来治疗这种破坏性疾病的疗法。此外，由于涉及MeCP2和出生后神经元成熟的重叠通路，该结果有望影响更广泛的自闭症和智力迟钝患者。公共卫生相关性：Rett综合征被认为是破解自闭症复杂遗传学的“罗塞塔石碑”，因为它是五种普遍发育障碍中唯一一种已知遗传原因的发育障碍。这一提议旨在了解Rett基因的产物MeCP2如何在出生后神经元的细胞核内运作，以调节学习和记忆中的重要基因调控事件。这些结果有望在理解和设计Rett综合征、自闭症和智力低下的未来治疗方法方面具有重要意义。

DESCRIPTION (provided by applicant): Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in MECP2, encoding methyl CpG binding protein 2 (MeCP2). RTT is the only autism-spectrum disorder with a known genetic cause and MECP2 mutations or expression defects are observed in other autism-spectrum neurodevelopmental disorders. Therefore, investigations of the role of MECP2 in the developing brain have broad relevance to mental retardation and autism. Since the discovery of MECP2 mutations as the genetic cause of RTT in 1999, the understanding of MeCP2 function has evolved. Although MeCP2 was predicted to be a global transcriptional repressor of methylated genes, MeCP2 is only required during postnatal brain development, when expression is elevated. To focus future experiments precisely on the role for MeCP2 that is deficient in the pathogenesis of RTT, a new model is proposed of MeCP2 as a dynamic neuronal nuclear factor that regulates genes involved in neuronal maturation through changes in sub-nuclear localization. The proposed experiments are designed to test the hypothesis that alternative splicing and post-translational modification of MECP2/Mecp2 exon 2 regulates sub-nuclear localization and differential protein association during neuronal maturation. Aim 1 will determine differences in sub-nuclear localization and protein association between MeCP2e1 and MeCP2e2 isoforms. Aim 2 will investigate changes in nuclear protein association and sub- nuclear localization of MeCP2 target genes. Aim 3 will identify novel targets of MeCP2 by genome-wide chromatin immunoprecipitation approaches and will test the relevance of each target gene to the pathogenesis of RTT. These results are expected to be significant in understanding the molecular pathogenesis of RTT and will be instrumental in designing future therapies to treat this devastating disorder. In addition, the results are expected to impact a broader spectrum of patients with autism and mental retardation because of overlapping pathways involving MeCP2 and post-natal neuronal maturation. PUBLIC HEALTH RELEVANCE: Rett syndrome has been considered a "Rosetta stone" for deciphering the complex genetics of autism because it is the only one of the five pervasive developmental disorders with a known genetic cause. This proposal seeks to understand how the product of the Rett gene, MeCP2, operates inside the nuclei of post-natal neurons to regulate important gene regulatory events in learning and memory. These results are expected to be significant in understanding and designing future therapies for Rett syndrome, autism, and mental retardation.