Title: Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis
Legend: Representative images (left) of adult neural progenitor cells (aNPCs) isolated from wild type (WT) and Mecp2S421A;S424A/y hippocampus with BrdU pulse labeling, followed by immunocytochemistry analysis. (middle) Representative images of Tuj1+ neurons differentiated from WT and Mecp2S421A;S424A/y aNPCs. (right) Representative images of GFAP+ astrocyte differentiated from WT and Mecp2S421A;S424A/y aNPCs.
Citation: Li, H., Zhong, X., Chau, K.F., Santistevan, N.J., Guo, W., Kong, G., Li, X., Kadakia, M., Masliah, J., Chi, J., Jin, P., Zhang, J., Zhao, X. and Chang, Q. (2014) Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signaling pathway. Nature Communications, PMCID: PMC4288926
Abstract: Neuronal activity regulates the phosphorylation states at multiple sites on MeCP2 in postmitotic neurons. The precise control of the phosphorylation status of MeCP2 in neurons is critical for the normal development and function of the mammalian brain. However, it is unknown whether phosphorylation at any of the previously identified sites on MeCP2 can be induced by signals other than neuronal activity in other cell types, and what functions MeCP2 phosphorylation may have in those contexts. Here we show that, in neural progenitor cells isolated from the adult mouse hippocampus, cell cycle-linked phosphorylation at serine 421 on MeCP2 is directly regulated by aurora kinase B, and modulates the balance between proliferation and neural differentiation through the Notch signaling pathway. Our findings suggest MeCP2 S421 phosphorylation may function as a general epigenetic switch accessible by different extracellular stimuli through different signaling pathways for regulating diverse biological functions in different cell types.
About the investigator: Chang’s long-term goal is to understand the molecular mechanism underlying DNA methylation-dependent epigenetic regulation of brain functions. His current focus is on the central role of MeCP2 (methyl-CpG binding protein 2), a molecular linker between DNA methylation and chromatin remodeling and transcriptional control, in the development and function of the nervous system. The functional significance of such a molecular linker is highlighted by the fact that mutations in the MECP2 gene cause Rett syndrome (RTT), a debilitating neurodevelopmental disorder that shares many features with autism. His studies include basic research aimed at understanding the function of MeCP2 and translational research aimed at understanding disease pathology and developing effective treatment. These two types of research are tightly interwoven—the need to solve a practical problem in translational research will always influence the direction of basic research; and fundamental mechanisms revealed by basic research will ultimately guide the effort in treating/curing the disease.