Comparative analysis of activins A and B in the adult mouse epididymis and vas deferens

Abstract

Activin A regulates testicular and epididymal development, but the role of activin B in the epididymis and vas deferens is unknown. Mouse models with reduced activin A ( and ), or its complete absence (), were investigated to identify specific roles of activins in the male reproductive tract. In 8-week-old mice, serum activin A decreased by 70%, with a 50% reduction of gene expression and protein in the testis, epididymis and vas deferens. Activin B and the activin-binding protein, follistatin, were similar to wild-type. Testis weights were slightly reduced in mice, but the epididymis and vas deferens were normal, while the mice were fertile. Activin A was decreased by 70% in the serum, testis, epididymis and vas deferens of mice and was undetectable in mice, but activin B and follistatin levels were similar to wild-type. In 6-week-old mice, testis weights were 60% lower and epididymal weights were 50% lower than in either or wild-type mice. The cauda epididymal epithelium showed infoldings and less intra-luminal sperm, similar to 3.5-week-old wild-type mice, but at 8 weeks, no structural differences in the testis or epididymis were noted between and wild-type mice. Thus, can compensate for in regulating epididymal morphology, although testis and epididymal maturation is delayed in mice lacking Crucially, reduction or absence of activin A, at least in the presence of normal activin B levels, does not lead to major defects in the adult epididymis or vas deferens.

Activins, follistatin and immunoregulation in the epididymis

“…Since Inhba −/− mice die at birth (Matzuk et al ., 1995a), we used heterozygous Inhba +/− mice, which show a 50% reduction in serum and tissue activin levels, to study the effects of activin A in the adult. It was shown that 50% of normal activin levels were sufficient to maintain epididymal structure and function in the adult, as the Inhba +/− mice were comparable to their wild‐type littermates in their epididymal morphology, overall epididymal gene expression and fertility (Wijayarathna et al ., 2018b).…”

“…It is significant, moreover, that the regional pattern of Ido1 expression follows that of the activins, which are constitutively biologically active, and not that of the TGF‐β subtypes, which are produced as latent precursors. It was noted that Ido1 did not decrease in response to reduced activin levels in the Inhba +/− mice, indicating that 50% of normal activin A, possibly in combination with activin B, is sufficiently robust to maintain Ido1 expression in the caput epididymis (Wijayarathna et al ., 2018b).…”

“…Cox2 expression was closely correlated with Fst and was highly abundant in the vas deferens, which may suggest that expression of this gene has an inverse relationship with the activins under normal conditions. While the expression of these genes was not significantly affected by the moderate increase or decrease in activin A in either the TghFST315 mouse model and Inhba +/− mouse model (Wijayarathna et al ., , 2018b), it remains to be determined how these genes may respond to larger alterations in activin activity in the male reproductive tract.…”

“…The factors that regulate the regional expression pattern of activin and follistatin in these tissues remain to be determined. The data from the Inha null mouse clearly indicate that activin in the caput epididymis is not derived from the testis (Wijayarathna et al ., ), but regulation by the presence of sperm or other testicular lumicrine factors may be involved (Xu et al ., ). The role of testicular or circulating androgens also remains to be determined.…”

Differential expression and localisation of TGF-β isoforms and receptors in the murine epididymis

“…As activins and TGF-βs both signal through SMAD2/3, one cannot rule out a contribution of activin signalling to the signal detected by Western blot analyses. However, this contribution is not expected to question the importance of the corpus region as ACTIVIN A was shown to be homogeneously present throughout the murine epididymis while ACTIVIN B was more present in the caput than in the cauda region 23,28 . On the contrary, TGF-β signalling may be underestimated in this study because TGF-β signalling pathways independent of SMAD, involving PI3K and various MAP kinases, have been described 29 .…”