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).
-
Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43NCBI Gene Expression Omnibus, GSE188903.
-
ingle-cell analysis of experience-dependent transcriptomic states in the mouse visual cortexhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE102827.
-
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.
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.
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.
Metrics
-
- 3,138
- views
-
- 577
- downloads
-
- 21
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43
eLife 11:e75230.
https://doi.org/10.7554/eLife.75230
Further reading
-
- Developmental Biology
Wnt signaling plays crucial roles in embryonic patterning including the regulation of convergent extension (CE) during gastrulation, the establishment of the dorsal axis, and later, craniofacial morphogenesis. Further, Wnt signaling is a crucial regulator of craniofacial morphogenesis. The adapter proteins Dact1 and Dact2 modulate the Wnt signaling pathway through binding to Disheveled. However, the distinct relative functions of Dact1 and Dact2 during embryogenesis remain unclear. We found that dact1 and dact2 genes have dynamic spatiotemporal expression domains that are reciprocal to one another suggesting distinct functions during zebrafish embryogenesis. Both dact1 and dact2 contribute to axis extension, with compound mutants exhibiting a similar CE defect and craniofacial phenotype to the wnt11f2 mutant. Utilizing single-cell RNAseq and an established noncanonical Wnt pathway mutant with a shortened axis (gpc4), we identified dact1/2-specific roles during early development. Comparative whole transcriptome analysis between wildtype and gpc4 and wildtype and dact1/2 compound mutants revealed a novel role for dact1/2 in regulating the mRNA expression of the classical calpain capn8. Overexpression of capn8 phenocopies dact1/2 craniofacial dysmorphology. These results identify a previously unappreciated role of capn8 and calcium-dependent proteolysis during embryogenesis. Taken together, our findings highlight the distinct and overlapping roles of dact1 and dact2 in embryonic craniofacial development, providing new insights into the multifaceted regulation of Wnt signaling.
-
- Developmental Biology
Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of principles of neural development.
