Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome

Significance Rett syndrome (RTT) is a severe neurological disease affecting girls in their early childhood. The underlying cause of most RTT cases is mutations in the gene methyl-CpG-binding protein 2 (MECP2). How the loss of MeCP2 function in the brain due to these mutations causes such severe neurological symptoms remains a mystery. Here, we show widespread aberrations in gene expression and anomalous patterns of alternative splicing, specifically when neurons of RTT mice are stimulated. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal stimulation in these RTT mice. Our findings suggest that MeCP2 is required for adjusting the robust changes in gene transcription and for proper regulation of alternative splicing during neuronal stimulation. Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. Here we reveal an aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity in a mouse model for RTT. Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.

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