Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, 80138 Naples, Italy.
Mol Biol Cell. 2012 Apr;23(8):1435-45. doi: 10.1091/mbc.E11-09-0784. Epub 2012 Feb 22.
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.
MECP2 蛋白优先与甲基化的 CpG 结合，并通过改变染色质结构来调节基因表达。功能失调的 MECP2 如何导致雷特综合征（RTT）患者的神经系统出现病理异常，其机制尚不清楚。为了更深入地了解 MECP2 在人类神经发生中的作用，我们比较了从 RTT 患者和健康供体中获得的间充质干细胞（MSC）的神经分化过程。我们进一步分析了携带部分沉默 MECP2 基因的人类神经母细胞瘤细胞系中的神经分化。在增殖和分化的 MSC 中观察到来自 RTT 患者的衰老和神经标记物表达减少，这表明 MECP2 蛋白活性受损可能会像在 RTT 患者中观察到的那样，损害神经分化。接下来，我们使用诱导表达系统在神经母细胞瘤细胞通过维甲酸处理诱导神经分化前后沉默 MECP2。这种方法用于测试 MECP2 失活是否会影响神经祖细胞的细胞命运和/或神经元分化和维持。总的来说，我们的数据表明，神经细胞命运和神经元维持可能会受到 MECP2 活性受损引发的衰老的干扰，无论是在神经分化之前还是之后。
