WNK1/HSN2 isoform and the regulation of KCC2 activity.

Abstract

Hereditary sensory and autonomic neuropathy type 2 is a rare autosomal recessive pathology presenting with early onset peripheral sensory defects. It arises from mutations affecting a specific isoform of the WNK1 kinase (with-no-lysine protein kinase 1) termed WNK1/HSN2. The role of WNK1 in the nervous system is not well understood. In our recent paper, we examined the effect of a pathological loss-of-function of the Wnk1/Hsn2 isoform on the development of the peripheral nervous system of the zebrafish embryo. Upon Wnk1/Hsn2 silencing using antisense morpholino oligonucleotides, we observed defects in the development of the sensory peripheral lateral line (PLL). Phenotypical embryos were also found to overexpress RNA for potassium-chloride cotransporter 2 (KCC2), a downstream target of WNK1 phosphorylation. Injection of recombinant mRNA for active KCC2, but not for inactive mutant KCC2-C568A, replicated the PLL defects observed in wnk1/hsn2 deficient animals, suggesting an essential role for WNK1/HSN2 in KCC2 regulation.