title: Reduced expression of MECP2 affects cell commitment and maintenance in neurons by triggering senescence: new perspective for Rett syndrome.
abstract: MECP2 protein binds preferentially to methylated CpGs and regulates gene expression by causing changes in chromatin structure. The mechanism by which impaired MECP2 activity can induce pathological abnormalities in the nervous system of patients with Rett syndrome (RTT) is not clearly understood. 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 carrying a partially silenced MECP2 gene. Senescence and reduced expression of neural markers were observed in proliferating and differentiating 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 after the induction of neural differentiation 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 maintenance. 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.
authors.affiliation: Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, 80138 Naples, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Squillaro
authors.forename: Nicola
authors.initials: N
authors.lastname: Alessio
authors.forename: Marilena
authors.initials: M
authors.lastname: Cipollaro
authors.forename: Mariarosa Anna Beatrice
authors.initials: MA
authors.lastname: Melone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Hayek
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.forename: Umberto
authors.initials: U
authors.lastname: Galderisi
mesh_terms: D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D009447:Neuroblastoma; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D015518:Rett Syndrome / Q000378:metabolism / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D002843:Chromatin; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D034741:RNA, Small Interfering; D014212:Tretinoin