Differential effects of spermatogenesis and fertility in mice lacking androgen receptor in individual testis cells

Abstract

Using a Cre-Lox conditional knockout strategy, we generated a germ cell-specific androgen receptor (AR) knockout mouse (G-AR ؊/y ) with normal spermatogenesis. Sperm count and motility in epididymis from AR ؊/y mice are similar to that of WT (G-AR ؉/y ) mice. Furthermore, fertility tests show there was no difference in fertility, and almost 100% of female pups sired by G-AR ؊/y males younger than 15 weeks carried the deleted AR allele, suggesting the efficient AR knockout occurred in germ cells during meiosis. Together, these data provide in vivo evidence showing male mice without AR in germ cells can still have normal spermatogenesis and fertility, suggesting the essential roles of AR during spermatogenesis might come from indirect cell-cell communication in a paracrine fashion. We then compared the consequences of AR loss in the spermatogenesis and fertility of G-AR ؊/y mice with two other testicular cell-specific AR ؊/y mice and total AR knockout male mice. The results provide clear in vivo evidence that androgen͞AR signaling in Sertoli cells plays a direct important role in spermatogenesis and in Leydig cells plays an autocrine regulatory role to modulate Leydig cell steroidogenic function. Total AR knockout male mice have the most severe defects among these mice. These contrasting data with G-AR ؊/y mice suggest AR might have different roles in the various cells within testis to contribute to normal spermatogenesis and male fertility in mice.germ cell ͉ knockout ͉ Sertoli cells ͉ Leydig cells

Neonatal Gonocyte Differentiation in Mongolian GerbilMeriones unguiculatusInvolves Asynchronous Maturation of Seminiferous Cords and Rapid Formation of Transitional Cell Stage

“…It is known that androgens and their cognate receptors are critical in determining the male phenotype and their roles in spermatogenesis have been widely investigated (Ghosh et al, 1991;O'shaughnessy et al, 2002;Yeh et al, 2002;Tsai et al, 2006;Wang et al, 2009). On the other hand, there is little information concerning the influence of androgen/AR signaling on germ cell differentiation during the fetal and neonatal periods.…”

Update on Male Hormonal Contraception: Is the Vasectomy in Jeopardy?

“…[23][24][25][26] In contrast, androgen receptors on germ cells and myoid cells appears to be less important in spermatogenesis as knock out models in these situations, do not impair spermatogenesis in a major way. 23,27 Compounds that are cell specific and influence Sertoli and Leydig cell androgen receptors could potentially be an excellent site of future male contraceptive thoughts. As described earlier, complete blockage of the androgen receptor with flutamide suppresses spermatogenesis.…”

Contribution of Recent Transgenic Models and Transcriptional Profiling Studies to Our Understanding of the Mechanisms by which Androgens Control Spermatogenesis

“…Furthermore, expression of the AR in germ cells is apparently not required for germ cell development. Germ cells in which the AR is defective develop normally when they are supported by AR-positive Sertoli cells [65,66] and mice with a germ cell specific AR knockout display normal fertility [67]. The only possibility that cannot be excluded is that androgens might affect germ cells via one of the mentioned alternative pathways that do not involve the AR.…”