The development of an inducible androgen receptor knockout model in mouse to study the postmeiotic effects of androgens on germ cell development

摘要

A mouse model with a Sertoli cell (SC)-selective ablation of the androgen receptor (AR)—the SCARKO mouse—demonstrated that the effects of androgens on spermatogenesis depend on the presence of an active AR in SC. This model has been extremely valuable in the study of the effects of androgens on the initiation of spermatogenesis. However, due to the early (prenatal) inactivation of the AR SCARKO mice develop a complete block in meiosis, making it impossible to study the effects of androgens on postmeiotic steps of germ cell development. It would therefore be of interest to develop a model in which the AR can be ablated at any chosen time point. Here we used a mouse line ubiquitously expressing a tamoxifen (TM)-inducible Cre recombinase to develop an inducible AR knockout model (iARKO). It is shown that treatment with TM (3 mg/day) for five consecutive days efficiently inactivates the AR in testicular tissue and decreases the expression of known AR-target genes in SC (Rhox5, Spinlw1) without markedly affecting testicular cell composition one day after the final injection. TM treatment did, however, decrease serum gonadotropin levels and the expression of several Leydig cell genes (StAR, Cyp17a1, Insl3), resulting in decreased testosterone levels. Nevertheless, the intratesticular testosterone concentration still far exceeds the estimated concentrations required to saturate the AR. It may be concluded that the study of androgen-responsive postmeiotic genes in SC may be feasible using a TM-inducible AR knockout model provided that appropriate controls are included correcting for off-target effects of TM.