The role of androgens in the control of spermatogenesis: lessons from transgenic models involving a Sertoli cell-selective knockout of the androgen receptor

Androgens play a key role in the control of spermatogenesis, but the cellular and molecular mechanisms involved remain poorly understood. The absence of androgen receptor (AR) expression in germ cells points to somatic cells as the most likely direct targets for androgen action. Sertoli cells are the primary candidates given their intimate morphological and functional interactions with developing germ cells and the fact that they express the AR in a cyclical fashion depending on the stages of spermatogenesis and their cognate androgen responsiveness. Isolated and cultured Sertoli cells have proven of limited help in the study of the effects and mechanisms of androgen action since they lose the expression and/or androgen responsiveness of many potentially relevant target genes. Novel transgenic models in which the AR is selectively ablated in Sertoli cells, such as the SCARKO mice, have made it possible to study the effects of the AR in Sertoli cells, while preserving their natural interactions with surrounding germ cells and somatic cells. These studies unambiguously identify the Sertoli cell as the major target for androgen action in the control of spermatogenesis. Moreover, they show that the effects of androgens on these cells are mainly or exclusively mediated by the classical AR. Selective ablation of this receptor during embryonic life results postpubertally in a block in germ cell meiosis, confirming that progression through meiosis is an early and sensitive target for androgen action. SCARKO mice and related models open a novel avenue to identify molecular mediators of androgen action involved in the control of germ cell development.