Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome

Zhifang Chen,Cheng Cheng,Shengnan Xia,Jingwen Lyu,Bo Yuan,Xiao Li,Xiuya Yu,Yinqi Shao,Zilong Qiu,Ran Zhang,Chen Dong,Wen-Hao Zhou,Dali Tong,Jingjing Zhou,Bin Yu

doi:10.1038/srep41701

Abstract

Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice. Interestingly, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 TG mice, which were critical for determining fates of adult hippocampal NSCs between the quiescence and activation. In summary, we found that MeCP2 plays a critical role in regulating fate determination of adult NSCs. These evidences further suggest that abnormal development of NSCs may play a role in the pathogenesis of the MECP2 duplication syndrome.

Highlights

Neural stem cells (NSCs) in the hippocampus generate new neurons throughout adulthood[7,8]
We found that radial glia-like NSCs (RGLs) (GFAP+/Nestin+) were increased in dentate gyrus (DG) of TG mice, in comparison to WT mice (Fig. 2a–h,q), and proliferating RGLs (GFAP+/Nestin+/Ki67+) appeared not to be different between WT and MECP2 TG mice (Fig. 2i–p,r)
Another research showed ectopically expressed Methyl CpG-binding protein 2 (MeCP2) in cultured neural progenitor cells (NPCs) was able to enhance neuronal differentiation and suppress astrocytic differentiation compared to the control after virus infection, suggesting a possible function of MeCP2 overexpression in NSCs differentiation[15]

Summary

Introduction

Neural stem cells (NSCs) in the hippocampus generate new neurons throughout adulthood[7,8]. Most of the adult NSCs are relatively quiescent. Previous work identified local parvalbumin (PV) positive interneurons play a critical role in controlling quiescent state of adult NSCs11. We showed that adult hippocampal quiescent NSCs were accumulated, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in hippocampus of MECP2 TG mice. We found that PV positive interneurons, which were identified as a critical niche component that dictates the adult hippocampal NSCs between the quiescence and activation[11], were significantly decreased in dentate gyrus (DG). These findings directly link MeCP2 to fate determination of adult NSCs in hippocampus and further suggest that adult neurogenesis may play a critical role in pathogenesis of autism spectrum disorders

Methods

Results

Conclusion