Spermatogonia and Sertoli cells appear as the primary targets of activin action in the adult human testis. Changes in testicular function associated with altered hormone levels may enhance ActRIIA mRNA and protein synthesis, thus modifying signalling by activin or other TGFbeta ligands within specific cells of the seminiferous epithelium.

Activin is a pleiotropic growth factor belonging to the transforming growth factor-b (TGFB) superfamily of signaling molecules. Regulated activin signaling is known to influence several steps in rodent male gamete differentiation. TGFB ligand isoforms, TGFB1-B3, also influence germ cell survival in the rodent testis at the onset of spermatogenesis and around the time of puberty. Given the importance of regulated activin and TGFB signaling in testis development and function, we sought to investigate the cellular production sites of activin/TGFB-signaling modulators in normal and dysfunctional adult human testes samples. Signaling transducers phosphorylated SMAD2/3, and signaling modulators SMAD6, MAN-1, inhibin a (INHA), and b-glycan were detected in Bouins fixed, paraffin-embedded adult human testis sections using immunohistochemistry. Additional samples examined were from testicular cancer patients and from normal men subjected to gonadotropin suppression with androgen-based contraceptives. Our findings identify distinct differences between normal and gonadotropin-deprived human testis in the expression and cellular localization of activin/TGFB-signaling modulators. The presence of a nuclear phosphorylated SMAD2/3 signal in all analyzed seminoma specimens indicated active activin/TGFB signaling. Moreover, a subset of seminoma specimens exhibited selective enhanced expression of b-glycan (4 out of 28 seminoma tumors), INHA (6 out of 28), and MAN-1 (6 out of 28), highlighting potential functional differences between individual tumors in their capacity to regulate activin/TGFB signaling. Within the heterogenous nonseminomas, expression of signaling modulators was variable and reflected the degree of somatic differentiation. Thus, synthesis of activin and TGFB-signaling modulators may be affected by spermatogenic disruption and altered hormone levels in the testis. Reproduction (2009) 138 801-811

Regulated transforming growth factor-beta (TGFbeta) superfamily signalling is an integral part of normal testicular development and the processes that enable the production of fertile sperm. Through shared utilization of receptors, signal transduction components and inhibitors, many ligands in this family exhibit functional overlaps; this facet of their function is critical to understand because these ligands are often co-expressed and, hence, they may compete with or compensate for one another, depending on the specific cellular context. This review describes particular germ cell maturation steps governed by bone morphogenetic proteins, glial cell line-derived neurotrophic factor and activins, focusing on data predominantly from rodent studies that implicate activin and other family members in modulation of gonocyte and spermatogonial stem cell development. We also review knowledge of the TGFbeta superfamily signalling components in the human testis, exploring their potential impact on the processes associated with disrupted gonocyte development and an enhanced risk of testicular cancer.