利用小鼠疾病模型研究DNA甲基化及非编码RNA在情感与记忆分子机制中的作用

脆性X综合症（Fragile X syndrome）和雷特综合症（Rett syndrome）是分别影响男、女性，已知、最普遍的遗传性、智障性神经疾病。它们的致病基因分别为Fmr1及Mecp2。Fmr1和Mecp2分别编码FMRP及MeCP2蛋白。FMRP主要抑制mRNA翻译。MeCP2是一个具甲基化CpG结合结构域的蛋白。FMRP可能通过microRNA来调控成年神经干细胞（ANSCs）的增殖与分化。MeCP2与ANSCs中DNA甲基化及非编码RNA具有相关性。考虑到ANSCs在情感形成与表达及学习与记忆中的重要作用，我们将利用小鼠模型研究ANSCs中FMRP、MeCP2、DNA甲基化及非编码RNA等表观遗传层次的调控在感情形成、表达及学习、记忆中的重要作用。我们的研究将有助于进一步揭示情感与记忆的分子机理及认识Fragile X syndrome和Rett syndrome的致病机理。

Fragile X syndrome and Rett syndrome are the most common inheritable diseases of mental retardation in male and female respectively. The disease gene of Fragile X syndrome is Fmr1, and for Rett syndrome, it is Mecp2. Fmr1 encodes a protein called FMRP, which inhibits mRNA translation. Mecp2 encodes MeCP2, which harbors a methyl CpG binding motif. FMRP could suppress mRNA translation and thus the proliferation and differentiation of adult neural stem cells (ANSCs) via microRNAs. MeCP2, DNA methylation, and noncoding RNAs could form regulatory networks in ANSCs. Considering the crucial roles of ANSCs in the formation and expression of emotion and in learning & memory, we are going to investigate the regulation among FMRP, MeCP2, and epigenetic regulators such as DNA methylation and noncoding RNAs for their roles in molecular evens underlaying emotion, learning, and memory in ANSCs using genetically manipulated mice. We hope that our research would aid efforts in further characterizing of molecular mechanisms of emotion and memory, and in understanding the molecular etiology of Fragile X syndrome and Rett syndrome.