Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome

Wei-Lun Hsu,Derek J C Tai,Eminy H Y Lee,Yen-Chen Liu,Yun-Li Ma

doi:10.1038/s41598-020-57745-w

Abstract

The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that re-expression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3β phosphorylation and increased level of β-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE.

Highlights

Methyl-CpG-binding protein 2 (MECP2) is an X chromosome-linked gene that encodes the MeCP2 protein
Results revealed that the MeCP2 T158A mutant mice showed significantly decreased number of crossovers in the activity chamber compared with WT mice, but this impairment was significantly rescued by lenti-Wnt[6] transduction (Fig. 1A)
Because we have presently found that enhanced Wnt[6] signaling ameliorated the behavioral deficits and restored BDNF expression in MeCP2 T158A mice and we have earlier found that Wnt[6] is regulated by MeCP2 SUMOylation[11], here we examined whether MeCP2 SUMOylation and Wnt[6] expression are regulated by EE

Summary

Introduction

Methyl-CpG-binding protein 2 (MECP2) is an X chromosome-linked gene that encodes the MeCP2 protein. Because all the MECP2 mutations associated with RTT show decreased MeCP2 SUMOylation level and because Wnt[6] mRNA level is dramatically reduced in MeCP2K412R sumo-mutant animals[11], these observations suggest that deficiency in Wnt[6] signaling and its downstream effectors may play a role in the pathogenesis of RTT. To test this hypothesis, we examined whether restoration of Wnt[6] signaling rescues the behavioral deficits in Mecp[2] mutant mice. We have adopted the MeCP2 T158A mutant mice as an animal model of RTT15

Methods

Results

Conclusion