Journal
JOURNAL OF CELL BIOLOGY
Volume 219, Issue 7, Pages -Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201909022
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Funding
- Wellcome Trust Senior Research Fellowships [102836/Z/13/Z, 214244/Z/18/Z]
- Multiple Sclerosis Society [697]
- Lister Institute Research Prize
- Wellcome Trust [214244/Z/18/Z] Funding Source: Wellcome Trust
- MRC [MR/P006272/1] Funding Source: UKRI
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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.
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