Tissue-specific androgen receptor knockout models. novel tools in the study of androgen action
Guido Verhoeven1, Evi Denolet1, Johannes Swinnen1, Philippa Saunders2, Richard Sharpe2 & Karel De Gendt1
Specific ablation of the androgen receptor (AR) in selected target cells prevents the major developmental defects inherent to generalised AR inactivation (Tfm, ARKO) and allows a detailed analysis of the contribution of defined cells and molecular pathways to more complex effects of androgens. We successfully applied this approach in the study of the role of androgens in the control of spermatogenesis, by developing a Cre/loxP-based mouse model with a Sertoli cell (SC)-selective knockout of the AR (SCARKO). SCARKO mice display a normal male phenotype and normal development of the urogenital tract. Testicular descent into the scrotum is normal but testis size reaches only 28% of that of wild type controls. AR expression is absent in the SC but present in Leydig and peritubular cells. SCARKO mice do not display a reduction in SC number but their SC are unable to support meiosis resulting in a reduction of spermatocytes, round spermatids and elongated spermatids to 64%, 3% and 0% respectively. Surprisingly, Leydig cell number is decreased but size is increased resulting in serum testosterone and LH levels that are undistinguishable from wild type controls. These data demonstrate unambiguously that SC play a key role in mediating the effects of androgens on germ cell development, that these effects depend on the classical AR and that progression through meiosis is an important target for androgen action. In an attempt to unravel the molecular mechanisms by which androgen action in SC controls meiosis we searched for differentially expressed genes in SCARKO and control testes at the onset of meiosis (day10) using microarray technology. Nearly 700 genes were found to be differentially expressed. For 40 of them the difference exceeded a factor 2. Functional analysis reveals that genes related to the protease/ antiprotease balance and to cell adhesion are overrepresented. The hypothesis is advanced that, at the initiation of spermatogenesis, androgens play a critical role in the control of tissue remodelling and cell-junction dynamics. These changes may be essential to create the appropriate environment needed for germ cell development.