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