Reply to Sun et al.: Roles of adult Leydig cell-derived activin A remain to be determined

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The complicated and sometimes confusing relationship between activin A and germ cell development has been studied for many decades both in vitro and in vivo. With regard to our publication in PNAS (1), the letter by Sun et al. (2) raises an excellent point in stressing the possible effects of adult Leydig cell-derived activin A on developing germ cells. In their letter, Sun et al. (2) provide a judicious reminder of an issue that we discussed many times during collection of this data—namely, what role does loss of adult Leydig cell-derived activin A play in the testicular phenotype that we observed in adult Inhba conditional knockout (cKO) mice? As presented in our PNAS article (1), conditional removal of Inhba within Amhr2-positive Leydig cells led to obvious fetal defects, including reduced coiling of testis cords and enlargement of testis cord diameter. By the time that the Inhba cKO mice were young adults, their testes exhibited enlarged seminiferous tubule diameter and various spermatogenic abnormalities. As Sun et al. (2) pointed out, the Amhr2-cre used to excise Inhba in fetal Leydig cells is also expressed in adult Leydig cells (3). Thus, the Inhba cKO mouse model that we developed is not able to clarify whether the adult testicular dysgenesis is caused solely by fetal defects or whether it additionally reflects the disruption of postnatal activin A production by adult Leydig cells.