Disruption to NKCC1 impairs the response of myelinating Schwann cells to neuronal activity and leads to severe peripheral nerve pathology

Kegel, L.; Marshall-Phelps, K. L.; Baraban, M.; Almeida, R. G.; Rubio-Brotons, M.; Klingseisen, A.; Benito-Kwiecinski, S.; Early, J. J.; Bin, J.; Livesey, M. R.; Poole, R. J.; Lyons, D. A.

doi:10.1101/757831

bioRxiv · 10.1101/757831

Disruption to NKCC1 impairs the response of myelinating Schwann cells to neuronal activity and leads to severe peripheral nerve pathology

Kegel, L.·Marshall-Phelps, K. L.·Baraban, M.·Almeida, R. G.·Rubio-Brotons, M.·Klingseisen, A.·Benito-Kwiecinski, S.·Early, J. J.·Bin, J.·Livesey, M. R.·Poole, R. J.·Lyons, D. A.

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Abstract

Myelinating Schwann cells of the peripheral nervous system (PNS) express numerous ion channels and transporters, and have the capacity to respond to neuronal activity. However, it remains unknown how the response of Schwann cells to neuronal activity affects peripheral nerve formation, health or function in vivo. Through a genetic screen in zebrafish, we identified a mutant, ue58, with severe disruption to the morphology of myelin along peripheral nerves and associated nerve oedema. Molecular analyses indicated that this phenotype was caused by the loss of function of a previously uncharacterized gene, slc12a2b, which encodes a zebrafish paralog of the solute carrier NKCC1. NKCC1 is a co-transporter of Na+, K+, and Cl- ions and water, typically from the extracellular space into cells. Upon impairing slc12a2b function, constitutively, or specifically in neurons or myelinating Schwann cells, we observed disruption to myelin and nerve oedema. Strikingly, we found that treatment of slc12a2b mutants with TTX completely prevented the emergence of these pathologies. Furthermore, TTX treatment rescued pathology in animals with cell-type specific loss of slc12a2b from myelinating Schwann cells. Together our data indicate that NKCC1 regulates ion homeostasis following neuronal activity and that this is required to maintain myelinated axon and peripheral nerve integrity.

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Kegel, L., Marshall-Phelps, K. L., Baraban, M., Almeida, R. G., Rubio-Brotons, M., Klingseisen, A., Benito-Kwiecinski, S., Early, J. J., Bin, J., Livesey, M. R., Poole, R. J., Lyons, D. A.. 2019-09-04. Disruption to NKCC1 impairs the response of myelinating Schwann cells to neuronal activity and leads to severe peripheral nerve pathology. https://doi.org/10.1101/757831

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