Hypogonadism associated withCyp19a1 (Aromatase) post-transcriptional upregulation inCelf1-KO mice

Abstract

CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1gene in mice causes male infertility due to impaired spermiogenesis, the post-meiotic 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 Celf1disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1was upregulated. Cyp19a1encodes 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 Cyp19a1mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1translation. We conclude that CELF1 downregulates Cyp19a1/Aromatasepost-transcriptionally 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.