The role of mecp2 phosphorylation in the development and function of the mouse brain

DNA methylation-dependent epigenetic mechanisms underlie the development and function of the mammalian brain. The X-linked MeCP2 functions as a molecular linker between DNA methylation, chromatin remodeling and transcription regulation. Mutations in the human MECP2 gene cause Rett syndrome. The phosphorylations of MeCP2 at Serine 80 (S80) and Serine 421/424 (S421/S424) are dynamically regulated in opposite manners by neuronal activity. To elucidate the in vivo function of MeCP2 phosphorylation, we have generated knockin mice with serine to alanine mutations to abolish MeCP2 phosphorylation. We show here that mice that lack S421/S424 phosphorylation perform better in hippocampus-dependent learning and memory tests, present enhanced long-term potentiation at two synapses in the hippocampus, and show increased excitatory synaptogenesis. At the molecular level, the S421/S424 phosphor mutant MeCP2 protein binds more tightly to several MeCP2 target gene promoters and alters the expression of these genes. In contrast, loss of S80 phosphorylation in mice leads to increased anxiety and impaired hippocampus-dependent spatial memory. Our results supply the first genetic evidence that MeCP2 phosphorylations are necessary for modulating dynamic functions of the adult mouse brain. Adult neurogenesis in the dentate gyrus occurs throughout the life and is important for the normal function of the adult hippocampus. Emerging evidence suggests the importance of DNA methylation-dependent regulation for adult neurogenesis. Surprisingly, we discovered that MeCP2 S421 phosphorylation is dynamically regulated in adult neural progenitor cells (aNPCs) by cell cycle. And mice that lack S421/S424 phosphorylation present decreased aNPCs proliferation and increased neuronal differentiation in vitro and in vivo. S421/S424 phosphor mutant aNPCs exhibit reduced Notch1 and Dll1 expression and decreased Notch signaling. Restoring Notch signaling level in phosphor mutant aNPCs is sufficient to rescue neurogenesis phenotypes. On the other hand, loss of S80 phosphorylation leads to increased proliferation and decreased neuronal differentiation of aNPCs. Our results suggest that MeCP2 S80 and S421/S424 phosphorylations play opposite roles in regulating adult neurogenesis. Taken together, we provide evidence from several aspects demonstrating the importance of MeCP2 S80 and S421/S424 phosphorylations for normal development and function of the nervous system.