MeCP2调控成年海马神经干细胞增殖分化的机制研究

Autism spectrum disorders are neurodevelopmental disorders characterised by severe deficits in socialisation, communication, and repetitive unusual behaviors. The incidence of these disorders has increased considerably in the past few years. Many genes were reported to be involved in ASD, such as NEUROLIGIN 3/4、SHANK3、NEUREXIN 1、MECP2、HOXA1、PTEN and UBE3A. Duplication of the MECP2 gene and hence increased MeCP2 protein dosage cause MeCP2 duplication syndrome, with a spectrum of phenotypes, including mental retardation, anxiety and autism. The involvement of MeCP2 in autism was confirmed, but the contribution of MeCP2 to autism is still unclear.. In our previous work, we found that adult hippocampal quiescent neural stem cells were significantly accumulated in transgenic mice comparing to wild type mice, and the neural progenitor cells were reduced in adult hippocampi of MECP2 transgenic mice. These data suggest that the proliferation and differentiation deficits of adult neural stem cells exist in the MECP2 transgenic mice. In addition, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 transgenic mice, which were critical for determining fates of adult hippocampal neural stem cells between the quiescence and activation.. We propose that MeCP2 acts through PV interneurons to modulate the proliferation and differentiation of neural stem cells, and ultimately leads to autism.. In present work, we would employ MECP2 transgenic mice, PV-Cre mice and PTEN conditional knockout or knockin mice to study the effect of the MeCP2-PTEN-PV pathway on the proliferation and differentiation of neural stem cells, and autistic behavior in mice. We aim to identity the role and potential mechanism of this MeCP2-PTEN-PV pathway in autism. The resulting work will provide new evidence and idea for the pathogenesis of autism and molecular targeted therapy.

孤独症谱系障碍是一类以社会交往障碍、语言交流障碍和重复刻板行为为主要特征的神经发育疾病。研究证实MeCP2基因拷贝数增加引发了MeCP2倍增综合征，参与孤独症的发病，但其详细作用机制尚不清楚。本研究前期工作发现，MeCP2过表达成年小鼠海马DG区的静息态神经干细胞数明显多于野生型小鼠，而过表达小鼠的神经前体细胞数则明显少于野生型小鼠的细胞数，这提示MeCP2过表达小鼠的成年神经干细胞存在增殖和分化的异常。我们还发现过表达小鼠DG区的PV神经元数明显少于野生型小鼠，这提示PV神经元可能参与了MeCP2调控神经干细胞的增殖分化。本研究拟采用MeCP2过表达小鼠、PV-Cre小鼠和PTEN条件性敲除/敲入小鼠，探讨MeCP2-PTEN-PV途径对神经干细胞增殖分化的影响，以及在小鼠孤独症行为表型中的作用，明确该途径在孤独症发生中的作用及机制，为揭示孤独症发病机制和分子靶向治疗提供新的依据和思路。