Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice

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dc.contributor.authorSánchez De La Torre, Aníbal
dc.contributor.authorAguado Sánchez, Tania
dc.contributor.authorHuerga-Gómez, Alba
dc.contributor.authorSantamaría, Silvia
dc.contributor.authorGentile, Antonietta
dc.contributor.authorChara, Juan Carlos
dc.contributor.authorMatute, Carlos
dc.contributor.authorMonory, Krisztina
dc.contributor.authorMato, Susana
dc.contributor.authorGuzmán Pastor, Manuel
dc.contributor.authorLutz, Beat
dc.contributor.authorGalve Roperh, Ismael
dc.contributor.authorPalazuelos Diego, Javier
dc.date.accessioned2023-11-23T12:27:02Z
dc.date.available2023-11-23T12:27:02Z
dc.date.issued2022
dc.description.abstractCannabinoids are known to modulate oligodendrogenesis and developmental CNS myelination. However, the cell-autonomous action of these compounds on oligodendroglial cells in vivo, and the molecular mechanisms underlying these effects have not yet been studied. Here, by using oligodendroglial precursor cell (OPC)-targeted genetic mouse models, we show that cannabinoid CB1 receptors exert an essential role in modulating OPC differentiation at the critical periods of postnatal myelination. We found that selective genetic inactivation of CB1 receptors in OPCs in vivo perturbs oligodendrogenesis and postnatal myelination by altering the RhoA/ROCK signaling pathway, leading to hypomyelination, and motor and cognitive alterations in young adult mice. Conversely, pharmacological CB1 receptor activation, by inducing E3 ubiquitin ligase-dependent RhoA proteasomal degradation, promotes oligodendrocyte development and CNS myelination in OPCs, an effect that was not evident in OPC-specific CB1 receptordeficient mice. Moreover, pharmacological inactivation of ROCK in vivo overcomes the defects in oligodendrogenesis and CNS myelination, and behavioral alterations found in OPC-specific CB1 receptor-deficient mice. Overall, this study supports a cellautonomous role for CB1 receptors in modulating oligodendrogenesis in vivo, which may have a profound impact on the scientific knowledge and therapeutic manipulation of CNS myelination by cannabinoids.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Biológicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio Economía y Transformación Digital (España)
dc.description.sponsorshipComunidad de Madrid
dc.description.sponsorshipInstitituto de Salud Carlos III
dc.description.sponsorshipEusko Jaurlaritza
dc.description.sponsorshipEuropean Commission
dc.description.sponsorshipMultiple Sclerosis Research Foundation (France)
dc.description.statuspub
dc.identifier.citationSánchez-de la Torre, A., Aguado, T., Huerga-Gómez, A. et al. Cannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice. Cell Death Dis 13, 585 (2022). https://doi.org/10.1038/s41419-022-05032-z
dc.identifier.doi10.1038/s41419-022-05032-z
dc.identifier.issn2041-4889
dc.identifier.officialurlhttps://doi.org/10.1038/s41419-022-05032-z
dc.identifier.urihttps://hdl.handle.net/20.500.14352/88941
dc.issue.number585
dc.journal.titleCell Death and Disease
dc.language.isoeng
dc.page.final13
dc.page.initial1
dc.publisherSpringer Nature
dc.relation.projectID(SAF2017–83516 and PID2020–112640RB-I00) (grants RTI2018–095311-B-I00 and SAF2016–75292-R)
dc.relation.projectID( grants 2016-T1/BMD-1060 and 2020–5 A/BMD-19728) ( contract PEJD-2017- PRE/BMD-3703)
dc.relation.projectID(AES 2018 grants PI18–00941 and PI18/00513)
dc.relation.projectID(grants IT1203–19 and PIBA19–0059)
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu615.9
dc.subject.cdu591.18
dc.subject.cdu612.8
dc.subject.keywordCannabinoid CB1 receptor
dc.subject.keywordOligodendrogenesis
dc.subject.keywordMyelination
dc.subject.ucmBioquímica (Biología)
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmNeurociencias (Biológicas)
dc.subject.unesco2403 Bioquímica
dc.subject.unesco2407 Biología Celular
dc.subject.unesco2490 Neurociencias
dc.titleCannabinoid CB1 receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number13
dspace.entity.typePublication
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