Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
- Johns Hopkins University School of Medicine, United States
- Johns Hopkins School of Medicine, United States
- Johannes Gutenberg University, Germany
- Max Planck Institute of Experimental Medicine, Germany
Abstract
Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43 deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult CNS induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.
Data availability
Bulk RNA-seq data of P30 FACS-isolated oligodendrocytes from Mobp-TDP43 and Mog-TDP43 mouse lines will be deposited to GEO. Processed data, including the raw count number, normalized counts, and FPKM values, are provided as Supplementary Data (Supplementary Data - Differential gene expression Excel file of bulk RNA-Seq.xlsx).
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Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43NCBI Gene Expression Omnibus, GSE188903.
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ingle-cell analysis of experience-dependent transcriptomic states in the mouse visual cortexhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102827.
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Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous systemhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE75330.
Article and author information
Author details
Gian C Molina-Castro
Funding
National Institutes of Health (R01 AG072305)
- Dwight E Bergles
National Multiple Sclerosis Society
- Dwight E Bergles
National Institutes of Health (F31NS110204)
- Dongeun Heo
European Research Council (MyeliNANO)
- Klaus-Armin Nave
Deutsche Forschungsgemeinschaft (DFG-TRR274)
- Klaus-Armin Nave
Target ALS
- Dwight E Bergles
Dr. Miriam and Sheldon G Adelson Medical Research Foundation
- Dwight E Bergles
Max-Planck-Institute of Experimental Medicine (open access funding)
- Wiebke Möbius
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Beth Stevens, Boston Children's Hospital, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations by the Institutional Animal Care and Use Committee (IACUC) of the Johns Hopkins School of Medicine under protocols (MO17M338, MO17M268, MO20M206, and MO20M344). All survival surgery was performed under isoflurane anesthesia, and every effort was made to minimize suffering. All terminal experiments were carried out under sodium pentobarbital anesthesia.
Version history
- Received: November 3, 2021
- Preprint posted: November 9, 2021 (view preprint)
- Accepted: March 18, 2022
- Accepted Manuscript published: March 21, 2022 (version 1)
- Version of Record published: March 31, 2022 (version 2)
Copyright
© 2022, Heo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
eLife 11:e75230.
https://doi.org/10.7554/eLife.75230
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