Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b

J Cell Biol. 2020 Jul 6;219(7):e201909022. doi: 10.1083/jcb.201909022.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

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*

Substances

  • Sodium Channel Blockers
  • Solute Carrier Family 12, Member 2
  • Zebrafish Proteins
  • Tetrodotoxin