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 reexpression 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. Methyl-CpG-binding protein 2 (MECP2) is an X chromosome-linked gene that encodes the MeCP2 protein. MeCP2 contains two major domains, the methyl-DNA binding domain and the transcriptional repression domain, which are both structurally conserved 1. MeCP2 was first found to function as a transcriptional repressor. It binds to the CpG island of methylated DNA and recruits co-repressors, such as the histone deacetylase (HDAC) complex, for transcriptional repression 2. But a later study has indicated that MeCP2 could also function as a transcriptional activator 3. MeCP2 plays an important role in a few neuro-developmental disorders, and one of them is the Rett syndrome (RTT) 1,4,5. RTT is a rare neurological and developmental disorder and it shares some common features with autism spectrum disorder 6. The RTT patients usually develop normally at their infant stage, but regression develops afterwards. The abnormal behaviors usually include motor function deficits, cognitive impairment and other symptoms associated with mental retardation 1,7. RTT is caused by mutations of the MECP2 gene. So far, more than 200 mutations have been identified that are associated with RTT 8. Some of these mutations are rare, but there are several most commonly seen mutations including T158M, R168X (X represents a premature stop codon), R133C, R106W, P152A, R306C and P376R, and the first three mutations account for approximately 32% of total RTT patients 9,10. Our previous study reveals that six out of these seven MECP2 mutations, except MECP2R168X as it lacks the C-terminal domain, show significantly decreased MeCP2 SUMOyl...