Follicle-stimulating hormone increases testicular Anti-Mullerian hormone (AMH) production through sertoli cell proliferation and a nonclassical cyclic adenosine 5'-monophosphate-mediated activation of the AMH Gene.
Anti-Müllerian hormone (AMH) production by testicular Sertoli cells is high before puberty and can be further induced by FSH. Our objective was to delineate the mechanisms by which FSH stimulates AMH production. Assay of serum AMH levels and histological morphometric analysis in prepubertal FSH-deficient transgenic mice showed that serum AMH and testicular mass were decreased owing to reduced Sertoli cell number. All parameters resumed normal values in mice treated with recombinant FSH. We also analyzed the ability of FSH and the factors involved in its signaling pathway to activate AMH transcription by transfecting AMH promoter-luc reporter constructs of different lengths in a prepubertal Sertoli cell line. Our results showed that FSH activates AMH transcription via adenylate cyclase, cAMP, and protein kinase A but involving a nonclassical cAMP-response pathway requiring nuclear factor-kappaB and activating protein 2 binding sites, which lie more than 1.9 kb upstream of the AMH transcription start site. This is the first report showing the importance of distant sequences in the regulation of AMH expression. We conclude that prepubertal testicular AMH production is increased by FSH stimulation through Sertoli cell proliferation and an enhancement of AMH gene transcription.
Lukas-Croisier
Céline
C
Centro de Investigaciones Endocrinológicas, Hospital de Niños, Gallo 1330, C1425EFD Buenos Aires, Argentina.
Lasala
Celina
C
Nicaud
Juliette
J
Bedecarrás
Patricia
P
Kumar
T Rajendra
TR
Dutertre
Martin
M
Matzuk
Martin M
MM
Picard
Jean-Yves
JY
Josso
Nathalie
N
Rey
Rodolfo
R
D000818:Animals; D054304:Anti-Mullerian Hormone; D001665:Binding Sites; D002455:Cell Division / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005640:Follicle Stimulating Hormone / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012708:Sertoli Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013735:Testicular Hormones / Q000235:genetics* / Q000378:metabolism*; D013737:Testis / Q000502:physiology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D016328:NF-kappa B; D013735:Testicular Hormones; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases