Neural Development of Methyl-CpG-Binding Protein 2-Null Embryonic Stem Cells : A System for Studing Rett Syndrome

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Mutations in methyl-CpG-binding protein 2 (MeCP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder that is the leading cause of mental retardation in females. We have developed a novel RTT model system that enables examination of the role of MeCP2 throughout development at the cellular level. Our study examining MeCP2 null ES cells during in vitro neuronal differentiation showed that MeCP2 is not essential for the maintenance or growth of undifferentiated cells or for the progression of neurogenesis. However, MeCP2 is required for the maturation of ES cell-derived neurons and for normal voltage-gated Na^+ currents and IAs. Furthermore, we showed that MeCP2 deficiency led to dramatically increased gliogenesis. Our novel experimental system has permitted us to address both important issues in MeCP2-related developmental biology and controversies regarding the pathogenesis of RTT, and may aid in the development of therapeutic strategies for RTT in the future.