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Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis
Author(s) -
Di Giacomo Daniele,
De Domenico Emanuela,
Sette Claudio,
Geremia Raffaele,
Grimaldi Paola
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.15-279034
Subject(s) - h3k4me3 , spermatogenesis , biology , cannabinoid receptor , epigenetics , retinoic acid , chromatin , meiosis , microbiology and biotechnology , medicine , endocrinology , receptor , genetics , agonist , gene , gene expression , promoter
Type 2 cannabinoid receptor (CB 2 ) has been proposed to play a pivotal role in meiotic entry of male germ cells, similar to retinoic acid (RA). In this study, we showed that activation of CB 2 with the specific agonist JWH133 [3‐(1‘,1‘‐dimethylbutyl)‐1‐deoxy‐8‐THC] (IC 50 10 –6 M) mimics epigenetic events induced by RA (IC 50 10 –7 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 hot‐spots 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 CB 2 antagonist delayed germ cell differentiation. Thus, both hyper‐ and hypostimulation of CB 2 disrupted the temporal dynamics of the spermatogenic cycle. These findings highlight the importance of proper CB 2 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