Investigating the role of Growth-differentiation factor 11 in neurodevelopmental and MECP2-related disorders

项目总结 甲基CpG结合蛋白2(MECP2)功能丧失突变或复制导致两个严重的 神经发育障碍：Rett综合征和MECP2重复综合征。而当 这些疾病的遗传原因是已知的，MECP2基因中断导致发病的机制 是未知的；这阻碍了靶向治疗的发展。用分泌因子治疗有 在MECP2疾病的临床前小鼠模型中显示出一定的疗效。确定候选人的隐秘因素 被MeCP2错误调节，从MeCP2缺失的小鼠模型中收集的转录组图谱被评估，并且 生长分化因子11(GDF11)是一种对MECP2-水平敏感的生长因子。GDF11是 在MeCP2缺失模型中下调，而在MECP2转基因模型中上调。与之相反的规定 MECP2对GDF11的错误调控暗示GDF11错误调控是RETT和RET之间的一种潜在共享机制 MeCP2重复综合征。GDF11是一种转化生长因子β家族的配体，是一种关键的 骨骼系统的图案化形态因子。然而，尽管大脑各处都有广泛的表达，但 GDF11在脑发育中的作用尚不清楚。 在这项研究中提出的工作将检验GDF11是大脑的关键形态因子的假设 其在MECP2-紊乱模型中的错误调节导致了MECP2-紊乱 表型。这一假设将通过以下具体目标进行检验： 1.测试通过病毒或遗传方法调节大脑特定剂量的GDF11本身是否会导致异常 神经学表型。 2.测试GDF11水平的正常化是否挽救了MECP2小鼠模型中的神经表型- 精神错乱。 3.通过模拟MECP2和GDF11之间的时间变化来检验MECP2和GDF11之间的调控关系 转录组对MECP2水平的扰动后，以确定初级基因表达的变化。 这项研究的结果将解决该领域的三个关键问题：1)GDF11对大脑是否重要 发展，2)GDF11水平的挽救确实改善了MECP2障碍小鼠模型的表型， 3)MECP2水平调节时，主要的基因表达变化是什么。

PROJECT SUMMARY Loss-of-function mutations or duplication in methyl-CpG binding protein 2 (MECP2) cause two severe neurodevelopmental disorders: Rett syndrome and MECP2 duplication syndrome, respectively. While the genetic cause of these disorders is known, the mechanism by which disruption in MECP2 leads to pathogenesis is unknown; this has prevented the development of targeted therapies. Treatment with secreted factors has shown some efficacy in preclinical mouse models of MECP2-disorders. To identify candidate secreted factors misregulated by MeCP2, transcriptome profiles collected from Mecp2-null mouse models were evaluated, and Growth differentiation factor 11 (GDF11) was identified as a growth factor sensitive to MECP2-levels. GDF11 is downregulated in Mecp2-null models, while upregulated in MECP2-transgenic models. The opposing regulation of GDF11 by MECP2 implicates GDF11 misregulation as one potential shared mechanism between Rett and MECP2 duplication syndromes. GDF11 is a transforming growth factor beta family ligand that is a critical patterning morphogen for the skeletal system. However, despite broad expression throughout the brain, the role of GDF11 in brain development is unknown. The work proposed in this fellowship will test the hypothesis that GDF11 is a key morphogen for brain development, and that its misregulation in models of MECP2-disorders contributes to MECP2-disorder phenotypes. This hypothesis will be tested through the following specific aims: 1. Test if modulating brain specific dose of GDF11 by viral or genetic methods itself causes aberrant neurological phenotypes. 2. Test if normalization of GDF11 levels rescues neurological phenotypes seen in mouse models of MECP2- disorders. 3. Test the regulatory relationship between MECP2 and GDF11 by modeling the temporal changes in the transcriptome after perturbation of MECP2-levels to identify primary gene expression changes. The results from this fellowship will address three key questions in the field: 1) is GDF11 dose important in brain development, 2) does rescue of GDF11-levels ameliorate phenotypes in mouse models of MECP2-disorders, and 3) what are the primary gene expression changes that occur upon modulation of MECP2 levels.