Journal Article

Neural stem cells from a mouse model of Rett syndrome are prone to senescence, show reduced capacity to cope with genotoxic stress, and are impaired in the differentiation process

Squillaro, Tiziana, Capasso, Stefania, Del Gaudio, Stefania, Riccitiello, Francesco, Cipollaro, Marilena, Alessio, Nicola, Di Bernardo, Giovanni, Melone, Mariarosa A. B., Peluso, Gianfranco, Galderisi, Umberto

2018

Overview

Several aspects of stem cell life are governed by epigenetic variations, such as DNA methylation, histone modifications, and chromatin remodeling. Epigenetic events are also connected with the impairment of stem cell functions. For example, during senescence, there are significant changes in chromatin organization that alter transcription. The MECP2 protein can bind methylated cytosines and contribute to regulating gene expression at one of the highest hierarchical levels. Researchers are particularly interested in this protein, as up to 90% of Rett syndrome patients have an MECP2 gene mutation. Nevertheless, the role of MECP2 in this disease remains poorly understood. We used a mouse model of Rett syndrome to evaluate whether residual MECP2 activity in neural stem cells (NSCs) induced the senescence phenomena that could affect stem cell function. Our study clearly demonstrated that the reduced expression of MECP2 is connected with an increase in senescence, an impairment in proliferation capacity, and an accumulation of unrepaired DNA foci. Mecp2 +/− NSCs did not cope with genotoxic stress in the same way as the control cells did. Indeed, after treatment with different DNA-damaging agents, the NSCs from mice with mutated Mecp2 accumulated more DNA damage foci (γ-H2AX+) and were more prone to cell death than the controls. Senescence in Mecp2 +/− NSCs decreased the number of stem cells and progenitors and gave rise to a high percentage of cells that expressed neither stem/progenitor nor differentiation markers. These cells could be senescent and dysfunctional. Rett syndrome: Mutation affects neural stem cells In Rett syndrome, neural stem cells lose some of their “stem cell like” properties, impairing brain functions. Patients with this rare neurological condition, almost exclusively girls, show impaired movement and speech beginning at 6–18 months of age. Mutations in the MECP2 gene are known to be involved, but the specifics are poorly understood. Umberto Galderisi at Temple University in Philadelphia and co-workers in Italy used a mouse model to trace how MECP2 mutations affect neural stem cells. They found that the mutated cells lost key stem cell abilities, including the capacity to renew themselves by dividing, and the ability to differentiate, or turn into other cell types. The cells were also highly susceptible to DNA damage and unable to repair it. These results improve our understanding of Rett syndrome and may help develop new treatments.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group,생화학분자생물학회
• Subject: 13/1 / 13/106 / 13/51 / 13/95 / 14/63 / 38/39 / 38/77 / 631/532 / 631/80/509 / 64/60 / 82/1 / 82/51 / Animals / Apoptosis - physiology / Biomedical and Life Sciences / Biomedicine / Blotting, Western / Cell Cycle - physiology / Cell death / Cell Differentiation - physiology / Cell Proliferation - physiology / Cells, Cultured / Cellular Senescence - physiology / Chromatin remodeling / Deoxyribonucleic acid / Disease Models, Animal / DNA / DNA damage / DNA Damage - physiology / DNA methylation / DNA Repair - physiology / Epigenetics / Female / Gene expression / Genotoxicity / Immunohistochemistry / MeCP2 protein / Medical Biochemistry / Methyl-CpG binding protein / Mice / Molecular Medicine / Neural stem cells / Neural Stem Cells - metabolism / Neural Stem Cells - pathology / Point mutation / Rett syndrome / Rett Syndrome - metabolism / Rett Syndrome - pathology / Senescence / Stem cell transplantation / Stem Cells / Transcription / 생화학