Mòdol Laura, Santos Daniel, Cobianchi Stefano, González-Pérez Francisco, López-Alvarez Víctor, Navarro Xavier
Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, E-08193 Bellaterra, Spain.
Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, E-08193 Bellaterra, Spain
J Neurosci. 2015 May 13;35(19):7414-27. doi: 10.1523/JNEUROSCI.4079-14.2015.
After peripheral nerve injury, axons are able to regenerate, although specific sensory reinnervation and functional recovery are usually worse for large myelinated than for small sensory axons. The mechanisms that mediate the regeneration of different sensory neuron subpopulations are poorly known. The Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) is particularly relevant in setting the intracellular chloride concentration. After axotomy, increased NKCC1 phosphorylation has been reported to be important for neurite outgrowth of sensory neurons; however, the mechanisms underlying its effects are still unknown. In the present study we used in vitro and in vivo models to assess the differential effects of blocking NKCC1 activity on the regeneration of different types of dorsal root ganglia (DRGs) neurons after sciatic nerve injury in the rat. We observed that blocking NKCC1 activity by bumetanide administration induces a selective effect on neurite outgrowth and regeneration of myelinated fibers without affecting unmyelinated DRG neurons. To further study the mechanism underlying NKCC1 effects, we also assessed the changes in mitogen-activated protein kinase (MAPK) signaling under NKCC1 modulation. The inhibition of NKCC1 activity in vitro and in vivo modified pJNK1/2/3 expression in DRG neurons. Together, our study identifies a mechanism selectively contributing to myelinated axon regeneration, and point out the role of Cl(-) modulation in DRG neuron regeneration and in the activation of MAPKs, particularly those belonging to the JNK family.
周围神经损伤后，轴突能够再生，尽管对于大型有髓感觉轴突而言，特定的感觉再支配和功能恢复通常比小型感觉轴突更差。介导不同感觉神经元亚群再生的机制尚不清楚。钠-钾-氯共转运体1（NKCC1）在设定细胞内氯离子浓度方面尤为重要。据报道，轴突切断后，NKCC1磷酸化增加对感觉神经元的神经突生长很重要；然而，其作用的潜在机制仍然未知。在本研究中，我们使用体外和体内模型来评估阻断NKCC1活性对大鼠坐骨神经损伤后不同类型背根神经节（DRG）神经元再生的差异影响。我们观察到，通过给予布美他尼阻断NKCC1活性对有髓纤维的神经突生长和再生产生选择性影响，而不影响无髓DRG神经元。为了进一步研究NKCC1作用的潜在机制，我们还评估了在NKCC1调节下丝裂原活化蛋白激酶（MAPK）信号传导的变化。体外和体内抑制NKCC1活性会改变DRG神经元中pJNK1/2/3的表达。总之，我们的研究确定了一种选择性促进有髓轴突再生的机制，并指出了Cl-调节在DRG神经元再生和MAPK激活中的作用，特别是那些属于JNK家族的MAPK。
