Delayed myelination in a mouse model of fragile X syndrome
Delayed myelination in a mouse model of fragile X syndrome
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DOI：
10.1093/hmg/ddt246
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发表时间：
2013-10-01
影响因子：
3.5
通讯作者：
Hampson, David R.
中科院分区：
文献类型：
--
作者：
Pacey, Laura K. K.;Xuan, Ingrid C. Y.;Hampson, David R.
脆性X综合征是自闭症最常见的遗传原因。脆性X智力低下蛋白（FMRP），这是缺乏脆性X，是一种mRNA结合蛋白，调节数百种不同的mRNA转录本的翻译。在成人大脑中，FMRP主要在神经元中表达;然而，它也在发育中的神经胶质细胞中表达，其中其功能还不清楚。在这里，我们表明，脆性X（Fmr 1）基因敲除小鼠显示异常的小脑轴突髓鞘形成早在出生后的第一周，大致相当于人类大脑发育的时间时，综合征的症状第一次变得明显（1-3岁）。在出生后第7天（PND），扩散张量磁共振成像显示，与野生型小鼠相比，Fmr 1小脑体积减少，同时髓鞘碱性蛋白表达减少80-85%，有髓轴突减少，髓鞘厚度减少，通过电子显微镜测量。PND 7时，Fmr 1小脑中蛋白聚糖NG 2的表达和PDGFR α +/NG 2+少突胶质前体细胞的数量均减少。尽管髓磷脂蛋白在PND 15时仍被抑制，但它们在PND 30时恢复了野生型水平。这些研究结果表明，少突胶质细胞前体细胞的成熟或功能受损诱导Fmr 1小鼠脑中髓鞘形成延迟。我们的研究结果支持了一个新的认识，即出生后早期大脑发育中的白色物质异常代表了脆性X综合征的潜在神经功能缺损。
Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFR alpha+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.