Adult testicular dysgenesis of Inhba conditional knockout mice may also be caused by disruption of cross-talk between Leydig cells and germ cells.

In a recent article, Archambeault and Yao (1) reported that genetic disruption of activin A resulted in a failure of fetal testiscord elongation and expansion because of decreased Sertoli cell proliferation. They uncovered a role of fetal Leydig cells during testis-cord morphogenesis through activin A signaling pathway. As shown in the study, Sertoli cell proliferation was obviously higher in the fetal testis of Inhba conditional knockout (cKO) mice compared with Smad4 cKO mice, whereas there was no significant difference in testis development and sperm production during adulthood between the two murine models. The discordant effect of activin A at embryonic stage and adulthood was attributable to the complexities of the TGF-β superfamily in male reproduction. However, we would add that activin A from Leydig cells also influences the differentiation of germ cell maturation in the postnatal testis. The anti-Müllerian hormone type 2 receptor-cre (Amhr2-cre) mouse strain was used to remove Inhba within fetal Leydig cells in this study. Nevertheless, Amhr2 is also present in adult Leydig cells (2), which are the sites of activin A subunit synthesis throughout testis development (3). Thus, loss of activin A in the adult Leydig cell should also be considered in the Inhba cKO murine model. It has been accepted that activin A controls juvenile testis growth by stimulating Sertoli cell proliferation. Moreover, studies have confirmed that activin A also influences germ cell maturation during postnatal development. First, it has been reported that a low level of activin A is necessary to the gonocyte–spermatogonia transition (4). Second, mRNA and protein levels of activin A declined rapidly 4 d postpartum, indicating that modulated synthesis of activin A is important during onset of murine spermatogenesis (3). Third, activin A could affect germ cell differentiation in the juvenile testis in vivo (5). We believe that activin A is also inactivated in adult Leydig cells, and the inactivation of activin A aggravates adult testicular dysgenesis in Inhba cKO mice. We fully agree with the authors that activin A produced by fetal Leydig cells signals to Sertoli cells and regulates their proliferation during fetal testis morphogenesis, but we would like to point out that the role of activin A originating from adult Leydig cells in the postnatal testicular development should not be ignored.