Abstract
Objective We examined expression of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), a basic-loop-helix transcription factor implicated in neuronal development and axonal health, in oligodendrocyte (OL) cultures and over the course of chronic experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS).
Methods We assessed OL ARNT2 expression in EAE compared with sham-immunized controls and also in OL primary cultures and over the course of dibutyryl cyclic adenosine monophosphate (dbcAMP)-mediated maturation of the immortalized Oli-neu cell line. We also tested the functional role of ARNT2 in influencing OL characteristics using small interfering RNA (siRNA).
Results ARNT2 is localized to Olig2+ cells in healthy spinal cord gray and white matter. Despite a significant expansion of Olig2+ cells in the white matter at peak disease, ARNT2 is reduced by almost half in OLs, along with a reduction in the percentage of ARNT2+/Olig2+ cells. Mature OLs in mixed cortical cultures or OLs matured from embryonic progenitors express negligible ARNT2. Similarly, Oli-neu cells express high levels of ARNT2, which are reduced following dbcAMP maturation. siRNA-mediated knockdown of ARNT2 affected OL viability, which led to an enrichment of myelin-producing OLs.
Conclusion The analysis of ARNT2 expression in OLs demonstrates that OL ARNT2 expression is altered in EAE and during OL maturation. Findings point to ARNT2 as an important mediator of OL viability and differentiation and warrant further characterization as a target for intervention in demyelinating disorders such as MS.
Glossary
- ARNT2=
- aryl hydrocarbon receptor nuclear translocator 2;
- bHLH=
- basic helix-loop-helix;
- cAMP=
- cyclic adenosine monophosphate;
- CFA=
- complete Freund adjuvant;
- CNPase=
- 2′,3′-cyclic nucleotide 3′-phosphodiesterase;
- CNTF=
- ciliary neurotrophic factor;
- dbcAMP=
- dibutyryl cyclic adenosine monophosphate;
- EAE=
- experimental autoimmune encephalomyelitis;
- FDR=
- false discovery rate;
- GFAP=
- glial fibrillary acidic protein;
- GM=
- gray matter;
- HIF-1α=
- hypoxia inducible factor-1 alpha;
- IgG=
- immunoglobulin G;
- L2F=
- log2 fold;
- MAG=
- myelin-associated glycoprotein;
- MBP=
- myelin basic protein;
- MOG=
- myelin oligodendrocyte glycoprotein;
- Npas4=
- neuronal PAS domain 4;
- OL=
- oligodendrocyte;
- OPC=
- OL precursor cell;
- PDGF=
- platelet-derived growth factor;
- siRNA=
- small interfering RNA;
- WM=
- white matter
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
↵* These authors contributed equally to the manuscript.
The Article Processing Charge was funded by the authors.
- Received October 19, 2019.
- Accepted in final form March 16, 2020.
- Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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