WNK1 is involved in Nogo66 inhibition of OPC differentiation

Zhang, Zhaohuan; Li, Jiaojiao; Wang, Qing-Jin; Zhao, Wei-Qian; Hong, Jeong-Hwa; Lou, Shujie; Xu, Xiaohui

doi:10.1016/j.mcn.2015.03.003

Cited by 15 publications

(16 citation statements)

References 33 publications

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“…Two phosphorylated residues are essential for WNK1 activation (Lenertz et al, ; Xu et al, ; Xu et al, ). However, contrary to our results, showing higher levels of phosphorylated and therefore activated WNK1 levels in Task1 ‐deficient cells, WNK1 knockdown has been shown to facilitate differentiation of oligodendrocytes after LINGO‐1 stimulation (Zhang et al, ; Zhang, Li, et al, ). Yang and colleagues recently revealed that the NOGO receptor (as part of the tripartite receptor with LINGO‐1 and p75NTR) regulates WNK1 gene and protein expression in PC12 cells.…”

Section: Discussioncontrasting

confidence: 99%

“…Taken together, absence of TASK1 channels in murine oligodendrocytes increases the amount of phosphorylated WNK1, which is known to be the active form of the kinase (McCormick & Ellison, ; Vitari et al, ; Xu et al, ). Thus, WNK1, a serine threonine kinase known to be involved in the downstream signaling of the myelination regulator LINGO‐1 (Zhang, Zhang, et al, ; Zhang, Li et al, ), might be involved in oligodendroglial TASK1 signalling.…”

Section: Resultsmentioning

confidence: 99%

“…This might be mediated via WNK1 promoting the synthesis of the signaling molecule PIP2 (An et al, ), which is critical for TASK1 channel regulation as has been shown by Bista and colleagues (Bista et al, ). Interestingly, co‐localization and interaction of WNK1 with LINGO‐1 in primary oligodendrocytes has been observed (Zhang et al, ; Zhang, Li, et al, ). LINGO‐1 is a well‐known transmembrane receptor, involved in the regulation of oligodendroglial differentiation, that came into focus as new revolutionary therapeutic target to promote CNS repair (Mi et al, ; Mi, Pepinsky, & Cadavid, ).…”

Section: Discussionmentioning

confidence: 99%

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The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

Albrecht

Korr

Nowack

et al. 2019

Glia

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In multiple sclerosis, demyelination occurs as a consequence of chronic autoimmunity in the central nervous system causing progressive neurological impairment in patients. After a demyelinating event, new myelin sheaths are formed by adult oligodendroglial progenitor cells; a process called remyelination. However, remyelination often fails in multiple sclerosis due to insufficient recruitment and differentiation of oligodendroglial precursor cells. A pivotal role for the twopore-domain potassium (K 2P ) channel, TASK1, has already been proven for an animal model of multiple sclerosis. However, the mechanisms underlying the TASK1-mediated effects are still elusive. Here, we tested the role of TASK1 channels in oligodendroglial differentiation and remyelination after cuprizone-induced demyelination in male mice. We found TASK1 channels to be functionally expressed on primary murine and human, pluripotent stem cell-derived oligodendrocytes. Lack of TASK1 channels resulted in an increase of mature oligodendrocytes in vitro as well as a higher number of mature oligodendrocytes and accelerated developmental myelination in vivo. Mechanistically, Task1-deficient cells revealed a higher amount of phosphorylated WNK1, a kinase known to be involved in the downstream signaling of the myelination regulator LINGO-1. Furthermore, we analyzed the effect of genetic TASK1 ablation or pharmacological TASK1 inhibition on disease-related remyelination. Neither channel inhibition nor lack of TASK1 channels promoted remyelination after pathological demyelination. In summary, we conclude that functional TASK1 channels participate in the modulation of differentiating oligodendroglial cells in a previously unknown manner. However, while being involved in developmental myelination our data suggest that TASK1 channels have no major effect on remyelination. K E Y W O R D S multiple sclerosis, myelination, oligodendrocyte, remyelination, TASK1 channel

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Section: Discussioncontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

Albrecht

Korr

Nowack

et al. 2019

Glia

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“…Primary neuronal cell culture and OGD/R model. Postnatal day 1 (P1) Sprague-Dawley rats were used for isolation of primary neuronal cells as previously described 12 . The rat primary cortical neurons were cultured in Neurobasal + B27 medium (Invitrogen) in a normoxic (21% O 2 , 74% N 2 and 5% CO 2 ) cell culture incubator at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury

Zhang

Wang

et al. 2020

Sci Rep

Self Cite

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Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up-and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.

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“…1,2,5,6 Blocking LINGO-1 function leads to robust remyelination in chemicaland immune-induced demyelination animal models. [7][8][9][10] The biological consequences of blocking LINGO-1 function have been substantiated using small interfering ribonucleic acid (siRNA), soluble versions of the LINGO-1 extracellular domain, anti-LINGO-1 antibodies, and LINGO-1-null mice. 1,6-8,10−14 LINGO-1 is a 581 amino acid transmembrane protein.…”

Section: Introductionmentioning

confidence: 99%

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

Hanf

Arndt

Liu

et al. 2020

mAbs

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2020) Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site, mAbs, 12:1, 1713648, ABSTRACT LINGO-1 is a membrane protein of the central nervous system (CNS) that suppresses myelination of axons. Preclinical studies have revealed that blockade of LINGO-1 function leads to CNS repair in demyelinating animal models. The anti-LINGO-1 antibody Li81 (opicinumab), which blocks LINGO-1 function and shows robust remyelinating activity in animal models, is currently being investigated in a Phase 2 clinical trial as a potential treatment for individuals with relapsing forms of multiple sclerosis (AFFINITY: clinical trial.gov number NCT03222973). Li81 has the unusual feature that it contains two LINGO-1 binding sites: a classical site utilizing its complementarity-determining regions and a cryptic secondary site involving Li81 light chain framework residues that recruits a second LINGO-1 molecule only after engagement of the primary binding site. Concurrent binding at both sites leads to formation of a 2:2 complex of LINGO-1 with the Li81 antigen-binding fragment, and higher order complexes with intact Li81 antibody. To elucidate the role of the secondary binding site, we designed a series of Li81 variant constructs that eliminate it while retaining the classic site contacts. These Li81 mutants retained the high affinity binding to LINGO-1, but lost the antibody-induced oligodendrocyte progenitor cell (OPC) differentiation activity and myelination activity in OPC-dorsal root ganglion neuron cocultures seen with Li81. The mutations also attenuate antibody-induced internalization of LINGO-1 on cultured cortical neurons, OPCs, and cells over-expressing LINGO-1. Together these studies reveal that engagement at both LINGO-1 binding sites of Li81 is critical for robust functional activity of the antibody. ARTICLE HISTORY

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WNK1 is involved in Nogo66 inhibition of OPC differentiation

Cited by 15 publications

References 33 publications

The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

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WNK1 is involved in Nogo66 inhibition of OPC differentiation

Cited by 15 publications

References 33 publications

The K2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

The K2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury

Functional activity of anti-LINGO-1 antibody opicinumab requires target engagement at a secondary binding site

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The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration

The K_2P‐channel TASK1 affects Oligodendroglial differentiation but not myelin restoration