Journal
FASEB JOURNAL
Volume 30, Issue 4, Pages 1453-1463Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.15-279034
Keywords
endocannabinoid system; histone methylation; meiosis; retinoic acid
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Funding
- Grant PRIN from the Italian Ministry of Education
- Agenzia Spaziale Italiana
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Type 2 cannabinoid receptor (CB2) has been proposed to play a pivotal role in meiotic entry of male germcells, similar to retinoic acid (RA). In this study, we showed that activation of CB2 with the specific agonist JWH133 [3-(1',1'-dimethylbutyl)-1-deoxy-8-THC] (IC50 10(-6) M) mimics epigenetic events induced by RA (IC50 1027 M) in spermatogonia. Both JWH133 and RA treatments stimulate the expression of the meiotic genes c-Kit and Stra8, by up-regulating H3K4me3 and down-regulating H3K9me2 levels in genomic regions flanking the transcription start site. Moreover, both agents increase the expression of Prdm9, the gene encoding a meiosis-specific histone, H3K4me3 methyltransferase, which marks hotspots of recombination in prophase I, thus resulting in a global increase in H3K4me3. Notably, prolonged administration of JWH133 to immature 7 dpp CD-1 mice induced an acceleration of the onset of spermatogenesis, whereas the specific CB2 antagonist delayed germ cell differentiation. Thus, both hyper- and hypostimulation of CB2 disrupted the temporal dynamics of the spermatogenic cycle. These findings highlight the importance of proper CB2 signaling for the maintenance of a correct temporal progression of spermatogenesis and suggest a possible adverse effect of cannabis in deregulating this process.-Di Giacomo, D., De Domenico, E., Sette, C., Geremia, R., Grimaldi, P. Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis. FASEB J. 30, 1453-1463 (2016). www.fasebj.org
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