Tanabe Katsuhisa, Gamo Kazushige, Aoki Shunsuke, Wada Keiji, Kiyama Hiroshi
Department of Anatomy and Neurobiology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
J Neurochem. 2007 May;101(4):1145-52. doi: 10.1111/j.1471-4159.2006.04432.x. Epub 2007 Feb 5.
We previously identified melanocortin receptor 4 (MC4R) in a search for genes associated with hypoglossal nerve regeneration. As melanocortins promote nerve regeneration after axonal injury, we investigated whether MC4R functions as a key receptor for peripheral nerve regeneration. In situ hybridization revealed that MC4R mRNA is induced in mouse hypoglossal motor neurons after axonal injury, whereas mRNAs for MC1R, MC2R, MC3R, and MC5R are not expressed either before or after nerve injury. This result was confirmed by RT-PCR. The level of MC4R mRNA expression increased significantly from day 3 after axotomy, reached a peak on day 5, and decreased to the control level on day 14. Similar induction of MC4R was observed in axotomized mouse dorsal root ganglia (DRGs). MC4R mRNA expression was induced exclusively among the MCR family in the L4-6 DRG after sciatic nerve injury. We further examined whether alpha-melanocortin stimulating hormone (alpha-MSH) promotes neurite elongation via MC4R. In mouse DRG neuron culture, alpha-MSH significantly promoted neurite outgrowth at a concentration of 10(-8) mol/L. This neurite-elongation effect was entirely inhibited by the addition of a selective MC4R blocker, JKC-363. Therefore, it is concluded that alpha-MSH could stimulate neurite elongation via MC4R in DRG neurons. The present results suggest that induction of MC4R is crucial for motor and sensory neurons to regenerate after axonal injury.
我们之前在寻找与舌下神经再生相关的基因时鉴定出了黑皮质素受体4（MC4R）。由于黑皮质素可促进轴突损伤后的神经再生，我们研究了MC4R是否作为周围神经再生的关键受体发挥作用。原位杂交显示，轴突损伤后小鼠舌下运动神经元中诱导了MC4R mRNA的表达，而MC1R、MC2R、MC3R和MC5R的mRNA在神经损伤前后均未表达。RT-PCR证实了这一结果。轴突切断术后第3天，MC4R mRNA表达水平显著升高，在第5天达到峰值，并在第14天降至对照水平。在切断轴突的小鼠背根神经节（DRG）中也观察到了类似的MC4R诱导现象。坐骨神经损伤后，MC4R mRNA表达仅在L4-6 DRG的MCR家族中被诱导。我们进一步研究了α-促黑素（α-MSH）是否通过MC4R促进神经突伸长。在小鼠DRG神经元培养中，α-MSH在浓度为10(-8) mol/L时显著促进了神经突生长。添加选择性MC4R阻滞剂JKC-363完全抑制了这种神经突伸长效应。因此，可以得出结论，α-MSH可通过DRG神经元中的MC4R刺激神经突伸长。目前的结果表明，MC4R的诱导对于运动和感觉神经元在轴突损伤后再生至关重要。
