The endocannabinoid system and pivotal role of the CB2 receptor in mouse spermatogenesis.
The exact role of the endocannabinoid system (ECS) during spermatogenesis has not been clarified. We used purified germ cell fractions representative of all phases of spermatogenesis and primary cultures of spermatogonia. This approach allowed the precise quantification of the cannabinoid receptor ligands, anandamide and 2-arachidonoylglycerol, and of the expression at transcriptional and transductional levels of their metabolic enzymes and receptors. Our data indicate that male mouse germ cells possess an active and complete ECS, which is modulated during meiosis, and suggest the presence of an autocrine endocannabinoid signal during spermatogenesis. Mitotic cells possess higher levels of 2-arachidonoylglycerol, which decrease in spermatocytes and spermatids. Accordingly, spermatogonia express higher and lower levels of 2-arachidonoylglycerol biosynthetic and degrading enzymes, respectively, as compared to meiotic and postmeiotic cells. This endocannabinoid likely plays a pivotal role in promoting the meiotic progression of germ cells by activating CB(2) receptors. In fact, we found that the selective CB(2) receptor agonist, JWH133, induced the Erk 1/2 MAPK phosphorylation cascade in spermatogonia and their progression toward meiosis, because it increased the number of cells positive for SCP3, a marker of meiotic prophase, and the expression of early meiotic prophase genes.
Grimaldi
Paola
P
Department of Public Health and Cellular Biology, University of Rome Tor Vergata, 00133 Rome, Italy. grimaldi@uniroma2.it
Orlando
Pierangelo
P
Di Siena
Sara
S
Lolicato
Francesca
F
Petrosino
Stefania
S
Bisogno
Tiziana
T
Geremia
Raffaele
R
De Petrocellis
Luciano
L
Di Marzo
Vincenzo
V
D000818:Animals; D001095:Arachidonic Acids / Q000096:biosynthesis; D063385:Cannabinoid Receptor Modulators / Q000096:biosynthesis / Q000378:metabolism*; D002186:Cannabinoids / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D063388:Endocannabinoids; D005455:Fluorescent Antibody Technique; D005989:Glycerides / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D049469:Meiotic Prophase I / Q000187:drug effects; D051379:Mice; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013091:Spermatogenesis / Q000187:drug effects; D013093:Spermatogonia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D005989:Glycerides; D053284:Polyunsaturated Alkamides; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C094503:glyceryl 2-arachidonate; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C078814:anandamide