Disease Modeling Using Embryonic Stem Cells: MeCP2 Regulates Nuclear Size and RNA Synthesis in Neurons

• DOI: 10.1002/stem.1180
• Publication Date: 2012-08-03T20:25:33Z
• Authors: Morteza Yazdani; Rubén Deogracias; Jacky Guy; Raymond A. Poot; Adrian Bird; Yves-Alain Barde
• Keywords: MeCP2; Rett Syndrome; Synaptophysin

Mutations in the gene encoding methyl-CpG-binding protein MECP2 are major cause of Rett syndrome, an autism spectrum disorder mainly affecting young females. MeCP2 is abundant chromatin-associated protein, but how and when its absence begins to alter brain function still far from clear. Using a stem cell-based system allowing synchronous differentiation neuronal progenitors, we found that MeCP2, size nuclei fails increase at normal rates during differentiation. This accompanied by marked decrease rate ribonucleotide incorporation, indicating early role regulating total transcription, not restricted selected mRNAs. We also levels brain-derived neurotrophic factor (BDNF) were decreased mutant neurons, while those presynaptic synaptophysin increased similar wild-type neurons. By contrast, nuclear size, transcription rates, BDNF remained unchanged astrocytes lacking MeCP2. Re-expressing neurons rescued phenotype as well levels. These results reveal new overall RNA synthesis course their maturation, line with recent findings reduced nucleolar developing mice Mecp2.