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DCC/netrin-1 regulates cell death in oligodendrocytes after brain injury

Cell Death & Differentiation (2022)Cite this article

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Abstract

Hallmark pathological features of brain trauma are axonal degeneration and demyelination because myelin-producing oligodendrocytes (OLs) are particularly vulnerable to injury-induced death signals. To reveal mechanisms responsible for this OL loss, we examined a novel class of “death receptors” called dependence receptors (DepRs). DepRs initiate pro-death signals in the absence of their respective ligand(s), yet little is known about their role after injury. Here, we investigated whether the deleted in colorectal cancer (DCC) DepR contributes to OL loss after brain injury. We found that administration of its netrin-1 ligand is sufficient to block OL cell death. We also show that upon acute injury, DCC is upregulated while netrin-1 is downregulated in perilesional tissues. Moreover, after genetically silencing pro-death activity using DCCD1290N mutant mice, we observed greater OL survival, greater myelin integrity, and improved motor function. Our findings uncover a novel role for the netrin-1/DCC pathway in regulating OL loss in the traumatically injured brain.

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Fig. 1: DCC receptors are expressed by oligodendrocytes (OLs) and are dependent on netrin-1 for survival.
Fig. 2: DCCD1290N mice have reduced OL cell death after CCI injury.
Fig. 3: DCCD1290N mice have improved cortical sparing and myelination after CCI injury.
Fig. 4: DCCD1290N mice have improved locomotor function after CCI injury.
Fig. 5: Schematic model of Netrin-1/DCC receptor function in the injured brain.

Data availability

The data analyzed during this study are included in this published paper and the supplemental data files. Additional supporting data are available from the corresponding authors upon reasonable request.

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Acknowledgements

The authors thank Maria L. Cepero, Maria M Quiala-Acosta, and Jose Mier for technical assistance and animal husbandry. Dr Oliver Umland was instrumental in the flow cytometry gating and analysis. We thank Drs Haritha Desu and Roberta Brambilla for reagents and guidance. Lastly, we thank Dr Pantelis Tsoulfas and Yan Shi for microscopy support. Graphical model was created in Biorender.com.

Funding

This work was supported by the Miami Project to Cure Paralysis, National Institute of Health/National Institute of Neurological Disorders and Stroke (NS098740, NS120028), Foundation Bettencourt (PM), ANR (PM) and ligue contre le cancer (PM), and the Lois Pope Life Foundation.

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  1. The Miami Project to Cure Paralysis, Department of Neurosurgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Madelen M. Díaz, Yanina Tsenkina, Dena Arizanovska & Daniel J. Liebl

  2. Apoptosis, Cancer and Development Laboratory – Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université de Lyon1, Lyon, France

    Patrick Mehlen

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PM, DJL, and YT conceived the study. PM provided technical and material support. MMD, YT, DA, DJL, and PM provided acquisition, analysis, interpretation of data, and statistical analysis. MMD and DJL drafted the paper. All authors read and approved the paper.

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Correspondence to Patrick Mehlen or Daniel J. Liebl.

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Díaz, M.M., Tsenkina, Y., Arizanovska, D. et al. DCC/netrin-1 regulates cell death in oligodendrocytes after brain injury. Cell Death Differ (2022). https://doi.org/10.1038/s41418-022-01091-z

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