Androgen action
            <i>via</i>
            testicular peritubular myoid cells is essential for male fertility

Welsh, Michelle; Saunders, Philippa T. K.; Atanassova, Nina; Sharpe, Richard M.; Smith, Lee B.

doi:10.1096/fj.09-138347

Cited by 215 publications

(231 citation statements)

References 46 publications

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“…S1). The Myh11-cre was effective at disrupting the Ar gene in PM cells (23). We confirmed that MYH11 is present in PM cells by immunostaining (Fig.…”

Section: Resultssupporting

confidence: 75%

“…Previous studies demonstrated that (i) cKO of the Ar gene in PM cells resulted in infertility (23), (ii) androgen response elements (AREs) were present in the promoter region of the Gdnf gene in mice (67), (iii) GDNF was essential for SSC maintenance in vitro (1,9,26), and (iv) PM cells isolated from human testes produced GDNF (68). We recently reported that (i) PM cells in adult mice produce GDNF, (ii) isolated PM cells from adult mice produce GDNF in response to T treatment, and (iii) SSCs co-cultured with T-treated PM cells are significantly more effective at repopulating the testes of germ cell-depleted mice following transplantation than SSCs co-cultured with untreated PM cells (10).…”

Section: Discussionmentioning

confidence: 99%

“…A conditional knockout (cKO) of the androgen receptor (Ar) gene in PM cells resulted in progressive loss of spermatogonia beginning at postnatal d 21, leading to disorganization of the seminiferous epithelium and infertility (23). This strongly suggested that androgens regulate genes in PM cells whose products are essential for SSC maintenance.…”

mentioning

confidence: 99%

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Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

Proc. Natl. Acad. Sci. U.S.A.

154

128

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Spermatogonial stem cells (SSCs) are a subpopulation of undifferentiated spermatogonia located in a niche at the base of the seminiferous epithelium delimited by Sertoli cells and peritubular myoid (PM) cells. SSCs self-renew or differentiate into spermatogonia that proliferate to give rise to spermatocytes and maintain spermatogenesis. Glial cell line-derived neurotrophic factor (GDNF) is essential for this process. Sertoli cells produce GDNF and other growth factors and are commonly thought to be responsible for regulating SSC development, but limited attention has been paid to the role of PM cells in this process. A conditional knockout (cKO) of the androgen receptor gene in PM cells resulted in male infertility. We found that testosterone (T) induces GDNF expression in mouse PM cells in vitro and neonatal spermatogonia (including SSCs) co-cultured with T-treated PM cells were able to colonize testes of germ cell-depleted mice after transplantation. This strongly suggested that T-regulated production of GDNF by PM cells is required for spermatogonial development, but PM cells might produce other factors in vitro that are responsible. In this study, we tested the hypothesis that production of GDNF by PM cells is essential for spermatogonial development by generating mice with a cKO of the Gdnf gene in PM cells. The cKO males sired up to two litters but became infertile due to collapse of spermatogenesis and loss of undifferentiated spermatogonia. These studies show for the first time, to our knowledge, that the production of GDNF by PM cells is essential for undifferentiated spermatogonial cell development in vivo.spermatogonial stem cell | stem cell niche | male fertility | spermatogenesis | conditional gene targeting T he seminiferous epithelium is separated by tight junctions between Sertoli cells into a luminal compartment containing spermatocytes and spermatids and a basal compartment containing spermatogonial stem cells (SSCs) and spermatogonia. The basal compartment is bounded above and on the sides by Sertoli cells and below by the basement membrane of the seminiferous tubule and a layer of peritubular myoid (PM) cells. SSCs are thought to reside in a microenvironmental niche in the basal compartment, where extrinsic cues influence their decision to either self-renew or enter the pathway of spermatogonial development (1, 2). They are a minor fraction of the undifferentiated spermatogonia in the basal compartment. The other undifferentiated spermatogonia (progenitors) give rise to differentiating spermatogonia that proliferate mitotically to progress on a developmental pathway toward becoming spermatocytes (3, 4). Our current understanding of the progression of SSCs to differentiating spermatogonia comes mainly from cell kinetic studies, germ cell transplantation assays, and the use of molecular markers that identify different populations of spermatogonia.The leading model for spermatogonial development specifies that when SSCs divide, they either self-renew by becoming two type A-single (A s ) spermato...

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“…S1). The Myh11-cre was effective at disrupting the Ar gene in PM cells (23). We confirmed that MYH11 is present in PM cells by immunostaining (Fig.…”

Section: Resultssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Chen

Willis

Eddy

2016

Proc. Natl. Acad. Sci. U.S.A.

154

128

View full text Add to dashboard Cite

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“…There is no means of specifically targeting KO of Ar in the adult Leydig stem cells, because the only presently known markers are COUP-TFII and AR, both of which are also expressed in peritubular myoid cells, and KO of Ar in the latter has phenotypic consequences, including on adult Leydig cells (38,39). We, therefore, investigated development of adult Leydig stem cells in complete ArKO mice.…”

Section: Resultsmentioning

confidence: 99%

“…Male congenic C57BL/6J mice hemizygous for an aP2-Cre transgene (37) were mated to homozygous R26R-EYFP females (73). The +/aP2-Cre:+/R26R-EYFP and +/+ :+/R26R-EYFP (control) male offspring from these matings were genotyped as previously described (38).…”

Section: -Hsd3mentioning

confidence: 99%

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Kilcoyne

Smith

Atanassova

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

160

135

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Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.adult Leydig stem/progenitor cells | compensated Leydig cell failure | GATA4 | ethane dimethane sulfonate

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Microenvironmental signals govern the cellular identity of testicular macrophages

Meinhardt

Wang

Schulz³

et al. 2018

Journal of Leukocyte Biology

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Testicular macrophages (TM) comprise the largest immune cell population in the mammalian testis. They are characterized by a subdued proinflammatory response upon adequate stimulation, and a polarization toward the immunoregulatory and immunotolerant M2 phenotype. This enables them to play a relevant role in supporting the archetypical functions of the testis, namely spermatogenesis and steroidogenesis. During infection, the characteristic blunted immune response of TM reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis. Local microenvironmental factors that determine the special phenotype of TM have just begun to be unraveled, and are discussed in this review.

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Androgen action via testicular peritubular myoid cells is essential for male fertility

Cited by 215 publications

References 46 publications

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Targeting theGdnfGene in peritubular myoid cells disrupts undifferentiated spermatogonial cell development

Fetal programming of adult Leydig cell function by androgenic effects on stem/progenitor cells

Microenvironmental signals govern the cellular identity of testicular macrophages

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