Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling
Open accessAbstract
Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.
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Pathway analyses based on cell type-specific significant DNAm changes associated with cannabis use implicated pathways such as the Slit-Robo signalling (granulocytes), the ErbB signalling pathway (T-cell) and pathways involved in DNA repair (B-cell).
“Interestingly, the pathway analyses based on the cell type-specific significant DNAm changes associated with CU implicated pathways such as the Slit-Robo signalling (granulocytes) under the regulatory control of the endocannabinoid system during brain cortical development (Alpár et al., 2014), the ErbB signalling pathway (T-cell) and pathways involved in DNA repair (B-cell) (Clark et al., 2021).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Alpár et al., 2014
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- Authors
- Alpár, A., Tortoriello, G., Calvigioni, D., Niphakis, M. J., Milenkovic, I., Bakker, J., Cameron, G. A., Hanics, J., Morris, C. V., Fuzik, J., Kovacs, G. G., Cravatt, B. F., Parnavelas, J. G., Andrews, W. D., Hurd, Y. L., Keimpema, E., & Harkany, T.
- Affiliations
- Karolinska Institutet (SE)
- Scripps Research Institute (US)
- Medical University of Vienna (AT)
- University of Aberdeen (GB)
- Semmelweis University (HU)
- Icahn School of Medicine at Mount Sinai (US)
- University College London (GB)
- Corresponding author
- Harkany, Tibor
- ORCID
- Venue
- Nature Communications
- Published
- 2014-07-17
- Volume
- 5
- Issue
- 1
- Pages
- 4421-4421
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4110686
- OpenAlex
- W2030496268
- Cited by
- 96
- References
- 64
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 3 · 2023: 9 · 2022: 17 · 2021: 4 · 2020: 21 · 2019: 6 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 10 · 2014: 1
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (089775)
- Karolinska Institutet
- National Institute on Drug Abuse (F31DA031559, R01DA023214, R01DA030359, DA023214, DA030359)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- endocannabinoids, 2-arachidonoylglycerol, axon guidance, cortical development, corticofugal axons, CB1 receptor, CB2 receptor, oligodendrocyte differentiation, prenatal drug exposure, human fetal brain
- MeSH terms
- Roundabout Proteins, Slit Homolog 2 Protein, Animals, Arachidonic Acids, Axons, Brain, Cells, Cultured, Corpus Callosum, Female, Glycerides, Humans, Immunohistochemistry, Male, Nerve Tissue Proteins, Pregnancy, Receptors, Immunologic, Mice, Knockout, Intercellular Signaling Peptides and Proteins, Receptor, Cannabinoid, CB1, Mice, Endocannabinoids
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