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首页> 外文期刊>Experimental Neurology >Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination
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Adult CNP::EGFP transgenic mouse shows pronounced hypomyelination and an increased vulnerability to cuprizone-induced demyelination

机译：成年CNP :: EGFP转基因小鼠表现出明显的髓鞘减少和对铜氮酮诱导的脱髓鞘的脆弱性增加

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CNP::EGFP transgenic mice, genetically engineered to express the enhanced green fluorescent protein (EGFP) under the control of the 2-3-cyclic nucleotide 3-phosphodiesterase (CNPase) promoter in oligodendroglial and Schwann cells, constitute a very important and widely used tool for the study of oligodendrocyte (OLG) development and function in young mice. Our results showed that CNP::EGFP mice were significantly more susceptible to CPZ-induced demyelination, as evaluated by MBP immunostaining, oligodendroglial progenitor cell (OPC) recruitment and astroglial, microglial and nestin response. This enhanced vulnerability was a consequence of their hypomyelination. CNP::EGFP control mice also displayed a significant decrease in corpus callosum (CC) thickness and MBP immunoreactivity. Morphometric analysis further showed a significant decrease in the frequency of myelinated axons, myelin turns (lamellae) and g-ratio carried out in the optic nerve (ON) and CC of CNP::EGFP, as compared to WT mice. Moreover, our results showed a decrease in the number of axons of small caliber, concomitantly with an increase in the number of axons of bigger size with more and enlarged mitochondria, which suggests a high energy demand. These findings and those displaying that MBP+ cells and NF200 staining in the CNP::EGFP cortex were more sparsely distributed provide evidence of axonal loss, which was supported by a decreased number of NeuN+ cells in the CA3 fields of the hippocampus. Transgenic mice also showed an increase in microglial and astroglial activation, accompanied by enhanced lipid peroxidation and recruitment of morphologically altered OPC. Finally, CNPase protein levels proved to be lower than MBP in the CC, which might indicate an altered pattern in myelin proteins with a CNPase deficiency. Behavioral analysis of adult CNP::EGFP transgenic mice supported our results, as it revealed a decrease in locomotion, exploratory activity and motor impairment, as compared to their WT littermates. Our data highlight the relevance of confronting results obtained in adult CNP::EGFP mice with those observed in WT mice. According to our findings, CNP::EGFP hypomyelination might be triggered by the cellular stress induced by the high level of EGFP expression in mature OLG. Adult CNP::EGFP mice could be considered a useful tool to evaluate future therapies for demyelinating diseases such as multiple sclerosis (MS), since these animals present chronic demyelination with axonal degeneration, a characteristic of such pathologies.
机译：CNP :: EGFP转基因小鼠在少突胶质和雪旺氏细胞中经过基因工程改造以在2-3-环核苷酸3-磷酸二酯酶（CNPase）启动子的控制下表达增强的绿色荧光蛋白（EGFP），这是非常重要且广泛使用的研究少儿少突胶质细胞（OLG）发育和功能的工具。我们的结果表明，通过MBP免疫染色，少突胶质祖细胞（OPC）募集以及星形胶质，小胶质和巢蛋白反应评估，CNP :: EGFP小鼠对CPZ诱导的脱髓鞘明显更敏感。这种增强的脆弱性是其髓鞘过少的结果。 CNP :: EGFP对照小鼠还显示call体（CC）厚度和MBP免疫反应性显着降低。形态计量学分析还显示，与WT小鼠相比，在CNP :: EGFP的视神经（ON）和CC中进行的髓鞘轴突，髓鞘转折（薄片）和g比率的频率显着降低。此外，我们的结果表明，小口径轴突的数量减少，伴随着线粒体更大和更大的轴突数量的增加，这表明对能量的需求很高。这些发现以及显示CNP :: EGFP皮质中MBP +细胞和NF200染色较稀疏的发现提供了轴突丢失的证据，这是由海马CA3区中NeuN +细胞数量减少所支持的。转基因小鼠还显示出小胶质细胞和星形胶质细胞激活的增加，同时伴随着脂质过氧化作用的增强和形态学改变的OPC的募集。最后，事实证明，CC中的CNPase蛋白水平低于MBP，这可能表明具有CNPase缺陷的髓磷脂蛋白发生了改变。成年CNP :: EGFP转基因小鼠的行为分析支持了我们的结果，因为与WT同窝仔相比，它揭示了运动，探索活动和运动障碍的减少。我们的数据强调了成年CNP :: EGFP小鼠与野生型小鼠中观察到的结果的相关性。根据我们的发现，成熟OLG中EGFP高水平表达引起的细胞应激可能触发CNP :: EGFP的髓鞘减少。成年的CNP :: EGFP小鼠可以被认为是评估未来的脱髓鞘疾病（如多发性硬化症（MS））疗法的有用工具，因为这些动物表现出慢性脱髓鞘和轴突变性，这是此类病理特征。

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