Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination
Analysis of congenital hypomyelinating Egr2Lo/Lo nerves identifies Sox2 as an inhibitor of Schwann cell differentiation and myelination
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DOI：
10.1073/pnas.0407836102
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发表时间：
2005-02-15
影响因子：
11.1
通讯作者：
Milbrandt, J
中科院分区：
文献类型：
--
作者：
Le, N;Nagarajan, R;Milbrandt, J
Egr 2是啮齿类动物外周神经髓鞘形成所需的转录因子，Egr 2的突变与人类先天性髓鞘形成不足神经病（CHN）相关。为了进一步研究其在髓鞘形成中的作用，我们产生了携带亚型Egr 2等位基因（Egr 2（Lo））的小鼠，其在出生后存活长达3周，这是啮齿动物中活跃髓鞘形成的时期。这些Egr 2（Lo/Lo）小鼠提供了研究Egr 2缺陷对雪旺细胞生物学的分子影响的机会，由于Egr 2缺失小鼠的围产期致死性，以前不可能进行分析。Egr 2（Lo/Lo）小鼠表现为CHN，表现为严重的髓鞘形成不足和周围神经的增殖雪旺细胞数量增加。坐骨神经基因表达谱在发展过程中和挤压损伤后与Egr 2（Lo/Lo）Schwarm细胞的比较显示，它们在发育上被阻滞，髓鞘形成相关基因下调，与未成熟和早幼髓鞘形成Schwann细胞相关的基因上调。Egr 2（Lo/Lo）Schwann细胞中异常升高的基因之一Sox 2编码一种转录因子，该转录因子对维持神经干细胞多能性至关重要。用Sox 2腺病毒或慢病毒感染的野生型雪旺细胞抑制髓鞘形成相关基因（例如，髓鞘蛋白零; Mpz），并且在体外不能使轴突髓鞘化，但是对β-神经调节蛋白具有增强的增殖反应。CHN小鼠模型的表征提供了对雪旺细胞分化的深入了解，并允许将Sox 2鉴定为髓鞘形成的负调节剂。
Egr2 is a transcription factor required for peripheral nerve myelination in rodents, and mutations in Egr2 are associated with congenital hypomyelinating neuropathy (CHN) in humans. To further study its role in myelination, we generated mice harboring a hypomorphic Egr2 allele (Egr2(Lo)) that survive for up to 3 weeks postnatally, a period of active myelination in rodents. These Egr2(Lo/Lo) mice provided the opportunity to study the molecular effects of Egr2 deficiency on Schwann cell biology, an analysis that was not possible previously, because of the perinatal lethality of Egr2-null mice. Egr2(Lo/Lo) mice phenocopy CHN, as evidenced by the severe hypomyelination and increased numbers of proliferating Schwann cells of the peripheral nerves. Comparison of sciatic nerve gene expression profiles during development and after crush injury with those of Egr2(Lo/Lo) Schwarm cells revealed that they are developmentally arrested, with down-regulation of myelination-related genes and up-regulation of genes associated with immature and promyelinating Schwann cells. One of the abnormally elevated genes in Egr2(Lo/Lo) Schwann cells, Sox2, encodes a transcription factor that is crucial for maintenance of neural stem cell pluripotency. Wild-type Schwann cells infected with Sox2 adenovirus or lentivirus inhibited expression of myelination-associated genes (e.g., myelin protein zero; Mpz), and failed to myelinate axons in vitro, but had an enhanced proliferative response to beta-neuregulin. The characterization of a mouse model of CHN has provided insight into Schwann cell differentiation and allowed the identification of Sox2 as a negative regulator of myelination.