title: NKCC1 Activation Is Required for Myelinated Sensory Neurons Regeneration through JNK-Dependent Pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Laura
authors.initials: L
authors.lastname: Mòdol
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Santos
authors.affiliation: 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.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0003-4588-8982
authors.initials: S
authors.lastname: Cobianchi
authors.affiliation: 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.
authors.forename: Francisco
authors.initials: F
authors.lastname: González-Pérez
authors.affiliation: 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.
authors.forename: Víctor
authors.identifier: http://orcid.org/0000-0002-1342-7818
authors.initials: V
authors.lastname: López-Alvarez
authors.affiliation: 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 xavier.navarro@uab.cat.
authors.forename: Xavier
authors.initials: X
authors.lastname: Navarro
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002034:Bumetanide / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000294:innervation; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D048670:MAP Kinase Kinase 4
keywords: JNK signaling; MAPKs; NKCC1; dorsal root ganglia; myelinated fibers; regeneration