Activin receptor subunits in normal and dysfunctional adult human testis

Dias, V. L.; Meachem, Sarah J; Meyts, Ewa Rajpert‐De; McLachlan, Robert I; Manuelpillai, Ursula; Loveland, Kate L

doi:10.1093/humrep/dem343

Cited by 30 publications

(33 citation statements)

References 36 publications

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“…Collectively, the enhanced TGFB ligand signaling conferred by b-glycan synthesis in round spermatids and enhanced activin signaling caused by preferential SMAD6 inhibition of BMP signaling may account for the particularly strong nuclear phosphorylated SMAD2/3 signal within 12-week testosterone or testosterone plus DMPA samples. These results are in agreement with our previous findings of enhanced ActRIIA protein production within the gonadotropin-deprived testis that could allow for enhanced activin and TGFB ligand signaling (Dias et al 2008).…”

Section: Discussionsupporting

confidence: 93%

“…6). These results are in accordance with our previous findings, which identify activin receptors in spermatogonia and Sertoli cells of the normal adult human testis (Dias et al 2008). Our findings also identify a subset of tumors in which expression of activin/TGFB transducers and antagonists is distinctly altered in a trend that correlates with either increased or decreased signaling.…”

Section: Discussionsupporting

confidence: 93%

“…We also described upregulation of a fourth activin receptor subunit, ActRIIA, as preinvasive CIS cells progress to malignant seminomas, indicating the capacity for aberrant activin signaling to occur in germ cell neoplasms (Dias et al 2008). Enhanced production of ActRIIA relative to normal testes was also detected in gonadotropin-deprived human testis samples, obtained following spermatogenic suppression in men treated with testosterone and depot progestin (McLachlan et al 2002, Dias et al 2008. The increased synthesis of ActRIIA in both seminomas and gonadotropin-deprived samples suggests the potential for activin signaling to be affected by changes in hormone levels.…”

Section: Introductionmentioning

confidence: 76%

“…Mice lacking the INHA subunit develop Sertoli cell tumors 3-4 weeks after birth, due to excessive activin production and signaling (Matzuk et al 1992). The absence of Sertoli cells in germ cell-derived tumors may also reflect excessive activin signaling, as the ActRIIA subunit is consistently up-regulated in seminomas (Dias et al 2008). The synthesis of INHA by a subset of seminomas may therefore engender in cells in these tumors the capacity to suppress activin signaling, with implications for the growth of seminoma cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous findings identified spermatogonia and Sertoli cells as the predominant targets of activin signaling in the adult human testis, based on the selective production of three activin receptor subunits ALK2, ACVR1B and ActRIIB in these cells (Dias et al 2008). We also described upregulation of a fourth activin receptor subunit, ActRIIA, as preinvasive CIS cells progress to malignant seminomas, indicating the capacity for aberrant activin signaling to occur in germ cell neoplasms (Dias et al 2008).…”

Section: Introductionmentioning

confidence: 86%

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Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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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

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

See 3 more Smart Citations

Analysis of activin/TGFB-signaling modulators within the normal and dysfunctional adult human testis reveals evidence of altered signaling capacity in a subset of seminomas

et al. 2009

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Smads and cell fate: Distinct roles in specification, development, and tumorigenesis in the testis

Itman

Loveland

2013

IUBMB Life

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According to the World Health Organization, a fertile man typically has a sperm count of 15 million per milliliter of semen. This spermatogenic capacity is determined by appropriate specification, proliferation, differentiation, and maturation of somatic and germ cells, events that begin during fetal development and continue throughout adulthood. These processes are orchestrated by the integration of signaling inputs from hormones and growth factors, including those of several transforming growth factor beta (TGFb) superfamily ligands. This review summarizes current knowledge of the Smad proteins, which serve functions central to fertility by transducing TGFb superfamily ligand signals in the testis. The importance of regulated Smad expression and differential utilization in signal transduction for fine-tuning cellular responses to ligands is discussed. We evaluate how primary cell culture studies and analyses of genetically modified mice have revealed distinct roles for specific Smads in primordial germ cell lineage specification, in determining the pace of testicular development and in controlling testicular tumorigenesis. This review also addresses the new insights gained from examining heterozygous mice that exhibit intriguing gene-dosage effects, outcomes that provide a new understanding of how TGFb superfamily ligands influence testis development and function. Finally, we consider the growing understanding that Smads mediate cross-talk with hormones to play a central role in determining male fertility and reproductive health. V C 2013 IUBMB Life, 65(2):85-97, 2013.

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