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神经元活性在 NKCC1b 缺失的情况下破坏有髓轴突的完整性。

Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b.

机构信息

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.

Electron Microscopy Core Unit, Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.

出版信息

J Cell Biol. 2020 Jul 6;219(7). doi: 10.1083/jcb.201909022.

DOI:10.1083/jcb.201909022
PMID:32364583
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7337504/
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.

摘要

通过在斑马鱼中的基因筛选，我们发现了一个突变体，该突变体由于一个以前未被描述的基因 slc12a2b 的突变，导致中枢神经系统和周围神经系统的髓鞘都被破坏，该基因预计编码一种 Na+、K+ 和 Cl-（NKCC）共转运蛋白 NKCC1b。 slc12a2b/NKCC1b 突变体在周围神经系统中表现出严重且进行性的病理学，其特征是髓鞘脱失和轴突-髓鞘界面处的周腔肿胀。神经元或髓鞘形成 Schwann 细胞中 slc12a2b/NKCC1b 的细胞特异性缺失重现了这些病理学变化。鉴于 NKCC1 对于离子动态平衡至关重要，我们询问了 slc12a2b/NKCC1b 突变体中髓鞘轴突的破坏是否受神经元活动的影响。令人惊讶的是，我们发现阻断神经元活动完全可以预防甚至可以挽救 slc12a2b/NKCC1b 突变体的病理学变化。总之，我们的数据表明 NKCC1b 对于维持轴突-髓鞘界面处神经元活动相关溶质动态平衡以及髓鞘轴突的完整性是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/f389be4c0be0/JCB_201909022_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/0ae123d3d7d1/JCB_201909022_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/c1ff28fe13a1/JCB_201909022_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/7c7b529bbb19/JCB_201909022_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/3e5d364ed777/JCB_201909022_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/f522f6e41317/JCB_201909022_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/7dabc8d9e992/JCB_201909022_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/10170448f5fb/JCB_201909022_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/e9263e4cd1b6/JCB_201909022_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/f389be4c0be0/JCB_201909022_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/0ae123d3d7d1/JCB_201909022_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/c1ff28fe13a1/JCB_201909022_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/7c7b529bbb19/JCB_201909022_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/3e5d364ed777/JCB_201909022_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/f522f6e41317/JCB_201909022_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/7dabc8d9e992/JCB_201909022_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/10170448f5fb/JCB_201909022_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/e9263e4cd1b6/JCB_201909022_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7d5b/7337504/f389be4c0be0/JCB_201909022_Fig4.jpg

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