DCC Confers Susceptibility to Depression-like Behaviors in Humans and Mice and Is Regulated by miR-218
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Backgroud Variations in the expression of the Netrin-1 guidance cue receptor DCC (deleted in colorectal cancer) appear to confer resilience or susceptibility to psychopathologies involving prefrontal cortex (PFC) dysfunction.Methods With the use of postmortem brain tissue, mouse models of defeat stress, and in vitro analysis, we assessed microRNA (miRNA) regulation of DCC and whether changes in DCC levels in the PFC lead to vulnerability to depression-like behaviors.Results We identified miR-218 as a posttranscriptional repressor of DCC and detected coexpression of DCC and miR-218 in pyramidal neurons of human and mouse PFC. We found that exaggerated expression of DCC and reduced levels of miR-218 in the PFC are consistent traits of mice susceptible to chronic stress and of major depressive disorder in humans. Remarkably, upregulation of Dcc in mouse PFC pyramidal neurons causes vulnerability to stress-induced social avoidance and anhedonia.Conclusions These data are the first demonstration of microRNA regulation of DCC and suggest that, by regulating DCC, miR-218 may be a switch of susceptibility versus resilience to stress-related disorders.
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Genes such as Est1, Cacna1c, and Dcc, associated with stress sensitivity and psychiatric disorders including MDD in humans, were significantly differentially methylated.
“Genes (such as Est1 , Cacna1c , and Dcc ) associated with stress sensitivity and psychiatric disorders, including MDD in humans, 51 were significantly differentially methylated.”
From Epigenetics and depression (2019) · cites this paper as [51]
The Introduction and Results (page numbers unavailable) link DCC to stress susceptibility and MDD in humans. The cited paper does not establish the same association for Est1 or Cacna1c. The citation follows the association clause; the statement that the genes were differentially methylated is not attributed to this source. (LLM, conf=0.86)
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References 48 · Cited by 153
- Authors
- Torres-Berrío, A., Lopez, J. P., Bagot, R. C., Nouel, D., Dal Bo, G., Cuesta, S., Zhu, L., Manitt, C., Eng, C., Cooper, H. M., Storch, K.-F., Turecki, G., Nestler, E. J., & Flores, C.
- Affiliations
- Douglas Mental Health University Institute (CA)
- The University of Queensland (AU)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Flores, Cecilia
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 81
- Issue
- 4
- Pages
- 306-315
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC5239724
- OpenAlex
- W2514630415
- Cited by
- 153
- References
- 48
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 30 · 2023: 17 · 2022: 15 · 2021: 19 · 2020: 14 · 2019: 17 · 2018: 8 · 2017: 8 · 2015: 1
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (MOP‐74709)
- National Institute of Mental Health (P50MH096890)
- National Institute on Drug Abuse (R01DA037911)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- DCC receptor, netrin-1, miR-218, microRNA regulation, depression, major depressive disorder, prefrontal cortex, pyramidal neurons, chronic stress, anhedonia, vulnerability to stress, resilience, postmortem brain
- MeSH terms
- DCC Receptor, Animals, Major Depressive Disorder, Humans, Male, Mice, Inbred C57BL, Receptors, Cell Surface, RNA, Messenger, Social Behavior, Stress, Psychological, Prefrontal Cortex, Pyramidal Cells, Tumor Suppressor Proteins, MicroRNAs, Cell Line, Tumor, Mice
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