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.

中文翻译：

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在缺乏 NKCC1b 的情况下，神经元活动会破坏有髓轴突的完整性


通过对斑马鱼的基因筛选，我们发现了一种中枢神经系统和三七总皂甙中髓鞘质受到破坏的突变体，该突变体是由先前未表征的基因 slc12a2b 的突变引起的，该基因预计编码 Na+、K+ 和 Cl− (NKCC) 协同转运蛋白 NKCC1b 。 slc12a2b/NKCC1b 突变体在 PNS 中表现出严重的进行性病理，其特征是轴突-髓磷脂界面处的髓鞘脱失和轴突周围空间肿胀。神经元或髓鞘雪旺细胞中 slc12a2b/NKCC1b 的细胞类型特异性缺失再现了这些病理学。鉴于 NKCC1 对于离子稳态至关重要，我们询问 slc12a2b/NKCC1b 突变体中有髓轴突的破坏是否受到神经元活动的影响。引人注目的是，我们发现阻断神经元活动可以完全预防甚至可以挽救 slc12a2b/NKCC1b 突变体的病理学。总之，我们的数据表明 NKCC1b 是维持轴突-髓磷脂界面处神经元活动相关的溶质稳态以及有髓轴突的完整性所必需的。