Testosterone regulates FGF-2 expression during testis maturation by an IRESdependent translational mechanism.

Irma G. Gonzalez-Herrera (1, 2) , Leonel Prado-Lourenco (1, 2) , Frédéric Pileur (1, 2) , Caroline Conte (1, 2) , Aurélie Morin (3) , Florence Cabon (3) , Hervé Prats (1, 2) , Stephan Vagner (1, 2) , Francis Bayard (1, 2) , Sylvie Audigier (1) , Anne-Catherine Prats (1, 2)

1 IFR 31 - IFR 31 Louis Bugnard
2 Hormones, facteurs de croissance et physiopathologie vasculaire
3 ODTS - Oncogénèse, différenciation et transduction du signal

Spermatogenesis is a complex process involving cell proliferation, differentiation and apoptosis. Fibroblast Growth Factor 2 (FGF-2) is involved in testicular function, but its role in spermatogenesis has not been fully documented. The control of FGF-2 expression particularly occurs at the translational level, by an internal ribosome entry site (IRES)-dependent mechanism driving the use of alternative initiation codons. To study IRES activity regulation in vivo, we have developed transgenic mice expressing a bicistronic construct coding for two luciferase genes. Here we show that the FGF-2 IRES is age-dependently activated in mouse testis, whereas EMCV or c-myc IRESs are not. Real time PCR confirms that this regulation is translational. By using immunohistological techniques, we demonstrate that FGF-2 IRES stimulation occurs in adult, but not in immature, type-A spermatogonias.This is correlated with activation of endogenous FGF-2 expression in spermatogonia, whereas FGF-2 mRNA transcription is known to decrease in adult testis. Interestingly, the FGF-2 IRES activation is triggered by testosterone and partially inhibited by siRNA directed against the androgen receptor. Two-dimensional analysis of proteins bound to the FGF-2 mRNA 5'UTR after UV cross-linking reveals that testosterone treatment correlates with the binding of several proteins. These data suggest a paracrine loop where IRES-dependent FGF-2 expression, stimulated by Sertoli cells in responseto testosterone produced by Leydig cells, would in turn activate Leydig function and testosterone production. In addition, nuclear FGF-2 isoforms could be involved in an intracrine function of FGF-2 in the start of spermatogenesis, mitosis or meiosis initiation. This report demonstrates that mRNA translation regulation by an IRES-dependent mechanism participates in a physiological process.

Mots clés: FGF-2; testis maturation; IRES; translation control; testosterone; transgenic mouse

Domaines: Cancer

Irma G. Gonzalez-Herrera, Leonel Prado-Lourenco, Frédéric Pileur, Caroline Conte, Aurélie Morin, et al.. Testosterone regulates FGF-2 expression during testis maturation by an IRESdependent translational mechanism.. FASEB Journal, 2006, 20 (3), pp.476-8. ⟨hal-00143497⟩