Neuritin mediates nerve growth factor-induced axonal regeneration and is deficient in experimental diabetic neuropathy
Neuritin mediates nerve growth factor-induced axonal regeneration and is deficient in experimental diabetic neuropathy
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DOI：
10.2337/db07-0895
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发表时间：
2008-01-01
期刊：
影响因子：
7.7
通讯作者：
Gardiner, Natalie J.
中科院分区：
文献类型：
--
作者：
Karamoysoyli, Eugenia;Burnand, Rebecca C.;Gardiner, Natalie J.
实验性和临床糖尿病神经病变中轴突再生都有缺陷，导致轴突末端缺失和神经元功能障碍。这种失败背后的机制还没有完全理解，但是，在神经营养支持和信号转导的赤字已included.Research设计和方法，我们调查了neuritin（也被称为候选可塑性基因15，cpg 15）的表达在感觉神经系统的控制大鼠和大鼠链脲佐菌素（STZ）诱导的糖尿病，使用微阵列PCR，蛋白质印迹和免疫细胞化学分析。neuritin在体外感觉神经元的功能作用进行了评估，使用沉默RNA。在背根神经节（DRG）的小直径的神经元的人口中表达的neuritin和顺行和逆行运输沿着在体内的坐骨神经。神经生长因子（NGF）治疗诱导的神经元在体外感觉神经元的neuritin的转录和翻译的增加。这种增加具有时间和剂量依赖性，并通过促分裂原活化蛋白激酶或磷脂酰肌醇-3激酶活化而发生。使用沉默RNA抑制neuritin废除了NGF介导的神经突生长，证明neuritin在介导再生中发挥了关键作用。在12周的STZ诱导的糖尿病大鼠的DRG和坐骨神经的神经轴突素水平降低，这些赤字在体内逆转治疗与NGF.CONCLUSIONS-Manipulation糖尿病的神经轴突素水平，因此可能提供一个潜在的目标，在神经病变的管理治疗干预。
OBJECTIVE-Axonal regeneration is defective in both experimental and clinical diabetic neuropathy, contributing to loss of axonal extremities and neuronal dysfunction. The mechanisms behind this failure are not fully understood; however, a deficit in neurotrophic support and signaling has been implicated.RESEARCH DESIGN AND METHODS-We investigated the expression of neuritin (also known as candidate plasticity gene 15, cpg15) in the sensory nervous system of control rats and rats with streptozotocin (STZ)-induced diabetes using microarray PCR, Western blotting, and immunocytochemical analysis. The functional role of neuritin in sensory neurons in vitro was assessed using silencing RNA.RESULTS-Neuritin was expressed by a population of small-diameter neurons in the dorsal root ganglia (DRG) and was anterogradely and retrogradely transported along the sciatic nerve in vivo. Nerve growth factor (NGF) treatment induced an increase in the transcription and translation of neuritin in sensory neurons in vitro. This increase was both time and dose dependent and occurred via mitogen-activated protein kinase or phosphatidylinositol-3 kinase activation. Inhibition of neuritin using silencing RNA abolished NGF-mediated neurite outgrowth, demonstrating the crucial role played by neuritin in mediating regeneration. Neuritin levels were reduced in both the DRG and sciatic nerve of rats with 12 weeks of STZ-induced diabetes, and these deficits were reversed in vivo by treatment with NGF.CONCLUSIONS-Manipulation of neuritin levels in diabetes may therefore provide a potential target for therapeutic intervention in the management of neuropathy.