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.
Highlights
Interactions between axons and myelinating glia (Schwann cells in the peripheral nervous system [PNS] and oligodendrocytes in the central nervous system [CNS]) underpin many aspects of nervous system formation, health, and function
Monocarboxylate transporters juxtaposed at the axon–myelin interface are thought to mediate the transfer of metabolic substrates from the myelinating oligodendrocyte to the axon through the periaxonal space (Saab et al, 2016; Fünfschilling et al, 2012)
We found that myelin made by Schwann cells along the posterior lateral line nerve was disrupted (Fig. 1, B and C)
Summary
Interactions between axons and myelinating glia (Schwann cells in the peripheral nervous system [PNS] and oligodendrocytes in the central nervous system [CNS]) underpin many aspects of nervous system formation, health, and function. Given the incomplete annotation of the genome of chromosome 8 at the mutant-linked locus harboring the NKCC1-like sequence, we independently targeted two regions of the candidate gene using CRISPR guide RNAs. Independent targeting of exon 1 or exon 26, where the causative mutation resided, resulted in severe disruption to myelin morphology, as assessed by Tg(mbp:EGFP-CAAX) (Fig. S4).
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