ZFIN ID: ZDB-PUB-200505-3
Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b
Marshall-Phelps, K.L.H., Kegel, L., Baraban, M., Ruhwedel, T., Almeida, R.G., Rubio-Brotons, M., Klingseisen, A., Benito-Kwiecinski, S.K., Early, J.J., Bin, J.M., Suminaite, D., Livesey, M.R., Möbius, W., Poole, R.J., Lyons, D.A.
Date: 2020
Source: The Journal of cell biology   219(7): (Journal)
Registered Authors: Almeida, Rafael, Kegel, Linde, Lyons, David A., Poole, Richard
Keywords: none
MeSH Terms:
  • Action Potentials
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Axons/drug effects
  • Axons/metabolism*
  • Axons/ultrastructure
  • Central Nervous System/drug effects
  • Central Nervous System/metabolism
  • Central Nervous System/pathology
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • Humans
  • Mutation
  • Myelin Sheath/drug effects
  • Myelin Sheath/metabolism*
  • Myelin Sheath/ultrastructure
  • Neurons/drug effects
  • Neurons/metabolism*
  • Neurons/ultrastructure
  • Peripheral Nervous System/drug effects
  • Peripheral Nervous System/metabolism
  • Peripheral Nervous System/pathology
  • Schwann Cells/drug effects
  • Schwann Cells/metabolism*
  • Schwann Cells/ultrastructure
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Signal Transduction
  • Sodium Channel Blockers/toxicity
  • Solute Carrier Family 12, Member 2/deficiency
  • Solute Carrier Family 12, Member 2/genetics*
  • Tetrodotoxin/toxicity
  • Zebrafish
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics*
PubMed: 32364583 Full text @ J. Cell Biol.
Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons.