MeCP2-PTEN调控神经干细胞增殖分化影响孤独症发生的分子机制

Autism seriously affects the normal emotional and intellectual development of adolescent. Previous studies showed that the copy number of MeCP2 gene was increased in the patients with autism. Moreover, mice with MeCP2 gene mutation had the characterization of autism. These data confirmed that MeCP2 have an important role in the occurrence and development of autism. However, the mechanism that MeCP2 affects autism is still unknown. PTEN regulate the proliferation and differentiation of neural stem cell. In our previous study, we found that inhibition MeCP2 decrease the expression of PTEN. So, we speculate that MeCP2 maybe play its role in the autism through the regulation of proliferation and differentiation of neural stem cell. In this study, the MeCP2 or PTEN conditional knockout mice and MeCP2 overexpression mice were used. The aims of the study are: 1. to clarify whether MeCP2 regulate the expression of PTEN by miR-137; 2. to observe the effects of MeCP2, miR137 and PTEN on proliferation and differentiation of neural stem cell; 3. to observe whether the regulation of miR137, PTEN improve the symptom of autism. In summary, our aim is to clarify the role and mechanism of MeCP2 and PTEN on occurrence and development of autism from the regulation of neural stem cell proliferation and differentiation. We hope to provide novel ways to intervene autism by the results of this study.

孤独症严重影响青少年情感和智力发育。既往在孤独症人群中发现MeCP2基因拷贝数增加，MeCP2基因突变小鼠具有孤独症表型，证实MeCP2参与孤独症的发生，但机制未明。PTEN参与神经干细胞增殖分化的调控，本课题组前期研究发现，抑制MeCP2降低PTEN表达，推测调控神经干细胞增殖分化可能是MeCP2参与孤独症发生的机制。本研究以中枢神经系统MeCP2和PTEN条件性敲除小鼠、MeCP2过表达小鼠为研究对象，采用体内和体外实验，1.确定MeCP2通过调控miR-137对PTEN表达的调节作用；2.研究MeCP2、miR-137与PTEN对神经干细胞增殖分化的影响；3.探索通过调控miR-137、PTEN水平是否能够改善孤独症小鼠模型的疾病表型。通过研究，从调控神经干细胞增殖分化的角度，阐明MeCP2、PTEN在孤独症发生中的作用，揭示MeCP2在孤独症发病中的机制，为孤独症干预提供新的思路。

早前研究发现甲基化CpG结合蛋白MeCP2在抑制基因表达中有重要作用。MeCP2突变会导致瑞特综合征和孤独症。肿瘤抑制基因PTEN在肿瘤和孤独症中发现突变。早前研究发现MeCP2和PTEN蛋白均在大脑发育中有重要作用。在本课题研究中，我们发现MeCP2和PTEN蛋白可以通过microRNA 相互作用。敲减MeCP2可以导致microRNA-137的上调，而microRNAs-137的高表达可以进而抑制了PTEN的表达，因此敲减MeCP2时PTEN表达降低。另外，我们发现在PTEN敲除的会导致CREB Ser133位的磷酸化，而Ser133的磷酸化会增加microRNA-132的表达。miR-132通过结合MeCP2 mRNA的3’UTR，抑制MeCP2的表达。通过本研究，我们发现两个与疾病相关的关键基因MeCP2和PTEN通过不同的机制相互作用，为今后研究在不同疾病中研究某个关键基因的突变导致其他重要基因的变化，从而导致不同的结果，提供新的思路。