In vitro studies suggest reduced expression of methyl cytosine protein binding 2 (MECP2) affects cell commitment and maintenance in neurons by triggering senescence, new perspective for Rett syndrome

Introduction: Methyl cytosine protein binding 2 (MECP2) binds preferentially to methylated CpGs and regulates gene expression by causing changes in chromatin struc- ture. The mechanism by which impaired MECP2 activity can induce pathological abnormalities in the nervous system of patients with Rett syndrome (RTT) remains unknown. Studies in different animal models have produced conflicting results. In a mouse model of RTT syndrome, the results indicate that MECP2 is involved in the maturation and maintenance of neurons, whereas in Xenopus embryos, MECP2 muta- tions seem to affect neural cell fate decisions. Material and methods: To gain further insight into the role of MECP2 in human neurogenesis, we compared the neural differentiation process in mesenchymal stem cells (MSCs) obtained from a RTT patient and from healthy donors. We further analyzed neural differentiation in a human neuroblastoma cell line carry- ing a partially silenced MECP2 gene. Results: Senescence and reduced ex- pression of neural markers were ob- served in proliferating and differen- tiating MSCs from the RTT patient, which suggests that impaired activity of MECP2 protein may impair neural differentiation, as observed in RTT patients. Next, we used an inducible expression system to silence MECP2 in neuroblastoma cells before and af- ter the induction of neural differenti- ation via retinoic acid treatment. This approach was used to test whether MECP2 inactivation affected the cell fate of neural progenitors and/or neuronal differentiation and mainte- nance. Conclusion: Overall, our data suggest that neural cell fate and neuronal maintenance may be perturbed by senescence triggered by impaired MECP2 activity either before or after neural differentiation.