title: Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.
abstract: CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Gaella
authors.initials: G
authors.lastname: Boulanger
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Cibois
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Justine
authors.initials: J
authors.lastname: Viet
authors.affiliation: Institut National pour la Recherche Agronomique UR1037, LPGP, Fish Physiology and Genomics, Rennes, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Fostier
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Deschamps
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pastezeur
authors.affiliation: Unité fonctionnelle d'Hormonologie, Pôle de Biologie, Centre d'Investigation Clinique INSERM 0203, Centre Hospitalier Universitaire de Rennes, Rennes, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Massart
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gschloessl
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France carole.gautier@univ-rennes1.fr luc.paillard@univ-rennes1.fr.
authors.forename: Carole
authors.initials: C
authors.lastname: Gautier-Courteille
authors.affiliation: Université de Rennes 1, Université Européenne de Bretagne, Institut Fédératif de Recherche 140, Rennes, France Centre National de la Recherche Scientifique UMR 6290, Institut de Génétique et Développement de Rennes, Rennes, France carole.gautier@univ-rennes1.fr luc.paillard@univ-rennes1.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Paillard
mesh_terms: D000818:Animals; D001141:Aromatase / Q000235:genetics*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D000067879:CELF1 Protein / Q000235:genetics* / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D004958:Estradiol / Q000096:biosynthesis; D007006:Hypogonadism / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000077289:Letrozole; D051379:Mice; D018345:Mice, Knockout; D009223:Myotonic Dystrophy / Q000209:etiology; D009570:Nitriles / Q000494:pharmacology; D011485:Protein Binding; D014176:Protein Biosynthesis; D013091:Spermatogenesis / Q000187:drug effects / Q000502:physiology; D013739:Testosterone / Q000097:blood / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D047072:Aromatase Inhibitors; D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D009570:Nitriles; D014230:Triazoles; D013739:Testosterone; D004958:Estradiol; D000077289:Letrozole; D001141:Aromatase; D019363:Cytochrome P-450 CYP1A1