Testosterone regulates FGF-2 expression during testis maturation by an IRES-dependent translational mechanism

FASEB J. 2006 Mar;20(3):476-8. doi: 10.1096/fj.04-3314fje. Epub 2006 Jan 19.

Abstract

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 and 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 is 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 response to 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Age Factors
  • Androgen Receptor Antagonists
  • Animals
  • Codon
  • Fibroblast Growth Factor 2 / biosynthesis
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / physiology*
  • Genes, Reporter
  • Genes, Synthetic
  • Leydig Cells / physiology*
  • Luciferases, Renilla / genetics
  • Male
  • Meiosis
  • Mice
  • Mice, Transgenic
  • Mitosis
  • Paracrine Communication
  • Peptide Chain Initiation, Translational / physiology
  • Protein Biosynthesis*
  • Protein Isoforms / physiology
  • RNA, Messenger / genetics*
  • RNA, Messenger / radiation effects
  • RNA, Small Interfering / pharmacology
  • Receptors, Androgen / genetics
  • Recombinant Fusion Proteins / physiology
  • Regulatory Sequences, Nucleic Acid*
  • Ribosomes / metabolism
  • Sertoli Cells / physiology*
  • Spermatogenesis / physiology*
  • Testis / growth & development
  • Testis / metabolism
  • Testis / physiology*
  • Testosterone / metabolism
  • Testosterone / pharmacology
  • Testosterone / physiology*
  • Ultraviolet Rays

Substances

  • 5' Untranslated Regions
  • Androgen Receptor Antagonists
  • Codon
  • Protein Isoforms
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Androgen
  • Recombinant Fusion Proteins
  • Fibroblast Growth Factor 2
  • Testosterone
  • Luciferases, Renilla