Enhanced artemin/GFRα3 levels regulate mechanically insensitive, heat-sensitive C-fiber recruitment after axotomy and regeneration.
Enhanced artemin/GFRα3 levels regulate mechanically insensitive, heat-sensitive C-fiber recruitment after axotomy and regeneration.
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DOI：
10.1523/jneurosci.2195-10.2010
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发表时间：
2010-12-01
期刊：
影响因子：
--
通讯作者：
Koerber HR
中科院分区：
文献类型：
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作者：
Jankowski MP;Rau KK;Soneji DJ;Anderson CE;Koerber HR
我们最近的研究表明，在隐神经横断和成功再生后，缺乏瞬时受体电位香草样蛋白1 （TRPV1）的皮肤多模伤害感受器（CPMs）对热刺激敏感，并且含有TRPV1的机械不敏感、热敏感的c -纤维（CHs）的患病率增加。目标源性神经营养因子水平在切除和再生后也有所提高。其中，神经损伤后毛爪皮肤中神经胶质细胞系源性神经营养因子（GDNF）家族成员artemin表达显著增强，其受体GDNF家族受体α3 （GFRα3）在L2/L3背根神经节（DRGs）中表达升高。在这项研究中，我们评估了增强的artemin/GFRα3水平对小鼠隐神经再生后皮肤CH神经元变化的作用。我们使用了一种新开发的sirna介导的体内敲低策略来特异性抑制损伤诱导的GFRα3的表达，并结合体外记录制备来检测损伤后不同类型功能定义的神经元的反应特征和神经化学表型。我们发现抑制GFRα3不影响腋切开术诱导的CPM阈值的降低，但暂时阻止了CH神经元的募集。Western blot和real-time PCR对毛后爪皮肤和隐神经再生后L2/L3 DRGs的分析表明，抑制潜在的初始损伤诱导的靶源性artemin信号增强的增加导致再生后TRPV1表达的动态变化。这些TRPV1表达的变化可能是神经再生后CH神经元功能改变的基础。
We have shown recently that following saphenous nerve transection and successful regeneration, cutaneous polymodal nociceptors (CPMs) lacking transient receptor potential vanilloid 1 (TRPV1) are sensitized to heat stimuli and that mechanically insensitive, heat-sensitive C-fibers (CHs) that contain TRPV1 increase in prevalence. Target-derived neurotrophic factor levels were also enhanced after axotomy and regeneration. In particular, the glial-cell line-derived neurotrophic factor (GDNF) family member artemin was found to be significantly enhanced in the hairy hindpaw skin and its receptor GDNF family receptor α3 (GFRα3) was increased in the L2/L3 dorsal root ganglia (DRGs) following nerve injury. In this study, we assessed the role of enhanced artemin/GFRα3 levels on the changes in mouse cutaneous CH neurons following saphenous nerve regeneration. We used a newly developed siRNA-mediated in vivo knockdown strategy to specifically inhibit the injury-induced expression of GFRα3 and coupled this with an ex vivo recording preparation to examine response characteristics and neurochemical phenotype of different types of functionally defined neurons after injury. We found that inhibition of GFRα3 did not affect the axotomy-induced decrease in CPM threshold, but transiently prevented the recruitment of CH neurons. Western blot and real-time PCR analysis of hairy hindpaw skin and L2/L3 DRGs after saphenous nerve regeneration suggested that inhibition of the potential initial injury-induced increase in enhanced target-derived artemin signaling resulted in dynamic changes in TRPV1 expression after regeneration. These changes in TRPV1 expression may underlie the functional alterations observed in CH neurons after nerve regeneration.