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

项目摘要 甲基-CpG结合蛋白2（MECP 2）的功能缺失突变或重复导致两种严重的 神经发育障碍：分别为Rett综合征和MECP 2重复综合征。而 这些疾病的遗传原因是已知的，MECP 2的破坏导致发病机制的机制 目前尚不清楚;这阻碍了靶向治疗的发展。用分泌因子治疗 在MECP 2-病症的临床前小鼠模型中显示出一些功效。鉴定候选分泌因子 由于MeCP 2的错误调节，评估了从Mecp 2缺失小鼠模型收集的转录组谱， 生长分化因子11（GDF 11）被鉴定为对MECP 2水平敏感的生长因子。GDF 11是 在Mecp 2-null模型中下调，而在MECP 2-转基因模型中上调。相反的规则 提示GDF 11的错误调节是Rett和GDF 11之间的一种潜在的共享机制。 MECP 2复制综合征。GDF 11是一种转化生长因子β家族配体， 骨骼系统的形态形成原。然而，尽管在整个大脑中广泛表达， GDF 11在大脑发育中的作用尚不清楚。 这项研究将验证GDF 11是大脑的关键形态原的假设。 它在MECP 2障碍模型中的错误调节导致MECP 2障碍， 表型将通过以下具体目标检验这一假设： 1.测试通过病毒或遗传方法调节脑特定剂量的GDF 11本身是否会导致异常 神经学表型 2.测试GDF 11水平的正常化是否挽救了在MECP 2 - 2小鼠模型中观察到的神经学表型。 紊乱 3.通过对MECP 2和GDF 11的时间变化进行建模，测试MECP 2和GDF 11之间的调节关系。 在MECP 2水平扰动后，通过转录组的分析来鉴定主要基因表达变化。 这项研究的结果将解决该领域的三个关键问题：1）GDF 11剂量在大脑中重要吗？ 2）GDF 11水平的拯救是否改善了MECP 2病症的小鼠模型中的表型， 和3）在调节MECP 2水平时发生的主要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.