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Previous study has shown that re-expression of SUMO-modified MeCP2 in <jats:italic>Mecp2<\/jats:italic>-null neurons rescues synaptic and behavioral deficits in <jats:italic>Mecp2<\/jats:italic> conditional knockout mice, whereas about 12-fold decrease in <jats:italic>Wnt6<\/jats:italic> 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-3\u03b2 phosphorylation and increased level of \u03b2-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 <jats:italic>Bdnf<\/jats:italic> and <jats:italic>Igf-1<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-020-57745-w","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T11:02:58Z","timestamp":1579777378000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome"],"prefix":"10.1038","volume":"10","author":[{"given":"Wei-Lun","family":"Hsu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun-Li","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Chen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek J. C.","family":"Tai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eminy H. Y.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"57745_CR1","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1038\/13810","volume":"23","author":"RE Amir","year":"1999","unstructured":"Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature genetics 23, 185\u2013188, https:\/\/doi.org\/10.1038\/13810 (1999).","journal-title":"Nature genetics"},{"key":"57745_CR2","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1038\/30764","volume":"393","author":"X Nan","year":"1998","unstructured":"Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386\u2013389, https:\/\/doi.org\/10.1038\/30764 (1998).","journal-title":"Nature"},{"key":"57745_CR3","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1126\/science.1153252","volume":"320","author":"M Chahrour","year":"2008","unstructured":"Chahrour, M. et al. MeCP2, a key contributor to neurological diseases, activates and represses transcription. Science 320, 1224\u20131229, https:\/\/doi.org\/10.1126\/science.1153252 (2008).","journal-title":"Science"},{"key":"57745_CR4","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1146\/annurev-cellbio-092910-154121","volume":"27","author":"J Guy","year":"2011","unstructured":"Guy, J., Cheval, H., Selfridge, J. & Bird, A. The role of MeCP2 in the brain. Annual review of cell and developmental biology 27, 631\u2013652, https:\/\/doi.org\/10.1146\/annurev-cellbio-092910-154121 (2011).","journal-title":"Annual review of cell and developmental biology"},{"key":"57745_CR5","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.gde.2006.04.009","volume":"16","author":"P Moretti","year":"2006","unstructured":"Moretti, P. & Zoghbi, H. Y. MeCP2 dysfunction in Rett syndrome and related disorders. Current opinion in genetics & development 16, 276\u2013281, https:\/\/doi.org\/10.1016\/j.gde.2006.04.009 (2006).","journal-title":"Current opinion in genetics & development"},{"key":"57745_CR6","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1001\/archneurol.2011.149","volume":"68","author":"AK Percy","year":"2011","unstructured":"Percy, A. K. Rett syndrome: exploring the autism link. Archives of neurology 68, 985\u2013989, https:\/\/doi.org\/10.1001\/archneurol.2011.149 (2011).","journal-title":"Archives of neurology"},{"key":"57745_CR7","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1093\/hmg\/ddn380","volume":"18","author":"SE Swanberg","year":"2009","unstructured":"Swanberg, S. E., Nagarajan, R. P., Peddada, S., Yasui, D. H. & LaSalle, J. M. Reciprocal co-regulation of EGR2 and MECP2 is disrupted in Rett syndrome and autism. Human molecular genetics 18, 525\u2013534, https:\/\/doi.org\/10.1093\/hmg\/ddn380 (2009).","journal-title":"Human molecular genetics"},{"key":"57745_CR8","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1002\/humu.10243","volume":"22","author":"G Miltenberger-Miltenyi","year":"2003","unstructured":"Miltenberger-Miltenyi, G. & Laccone, F. Mutations and polymorphisms in the human methyl CpG-binding protein MECP2. 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