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

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&...

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Bibliographic Details
Published in:	Cell death and differentiation 2023-02, Vol.30 (2), p.397-406
Main Authors:	Díaz, Madelen M, Tsenkina, Yanina, Arizanovska, Dena, Mehlen, Patrick, Liebl, Daniel J
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis Brain Injuries Cell Death Colorectal carcinoma DCC protein DCC Receptor - metabolism Death receptors Demyelination Life Sciences Ligands Mice Myelin Nerve Growth Factors - genetics Nerve Growth Factors - metabolism Netrin-1 Netrin-1 - metabolism Netrins Neurodegeneration Neurons and Cognition Oligodendrocytes Oligodendroglia - metabolism Receptors, Cell Surface - metabolism Traumatic brain injury Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism
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Summary:	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 DCC 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.
ISSN:	1350-9047 1476-5403