Regulated Wnt/Beta-Catenin Signaling Sustains Adult Spermatogenesis in Mice1

Kerr, Genevieve; Young, Julia; Horvay, Katja; Abud, Helen E.; Loveland, Kate

doi:10.1095/biolreprod.112.105809

Cited by 72 publications

(59 citation statements)

References 45 publications

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“…For example, we detected the expression of Wnt3 in round spermatids and elongating spermatids, Wnt3a in round spermatids, Wnt5a in Leydig cells and peritubular myoid cells, Wnt7a in pachytene spermatocytes and round spermatids, and Wnt8b in round spermatids. These gene-expression patterns are compatible with previously published transcriptional profiling data (37)(38)(39).…”

Section: Sertoli Cells Secrete Wnt6 As a Paracrine Signal For Undiffesupporting

confidence: 89%

“…In addition, spermatid-specific β-catenin CKO mediated by Prm1-Cre has been shown to cause impaired fertility as a result of reduced sperm counts (50). Another group reported disrupted spermatogenesis in both loss-and gain-of-Wnt signaling function experiments using AhCre (37). However, it is difficult to compare these phenotypes to those observed by us because of differences in target cell types or leaky Cre activity before induction.…”

Section: Discussionmentioning

confidence: 81%

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Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

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

122

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Spermatogonial stem cells (SSCs) fuel the production of male germ cells but the mechanisms behind SSC self-renewal, proliferation, and differentiation are still poorly understood. Using the Wnt target gene Axin2 and genetic lineage-tracing experiments, we found that undifferentiated spermatogonia, comprising SSCs and transit amplifying progenitor cells, respond to Wnt/β-catenin signals. Genetic elimination of β-catenin indicates that Wnt/β-catenin signaling promotes the proliferation of these cells. Signaling is likely initiated by Wnt6, which is uniquely expressed by neighboring Sertoli cells, the only somatic cells in the seminiferous tubule that support germ cells and act as a niche for SSCs. Therefore, unlike other stem cell systems where Wnt/β-catenin signaling is implicated in self-renewal, the Wnt pathway in the testis specifically contributes to the proliferation of SSCs and progenitor cells.

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Section: Sertoli Cells Secrete Wnt6 As a Paracrine Signal For Undiffesupporting

confidence: 89%

Section: Discussionmentioning

confidence: 81%

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Takase

Nusse

2016

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

122

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“…However, during T-cell development, Sox13 also directly interacts with the lymphoid enhancer-binding factor (TCF/LEF) to cause repression of Wnt target gene expression [37]. Interestingly, the use of mouse models revealed that the Wnt signaling pathway is required for normal spermatogenesis [81] and that Wnt4 inhibits testosterone synthesis by repressing SF-1 (NR5A1)/beta-catenin synergy in Leydig cells [82]. Thus, Sox13 may regulate steroidogenic gene (A) (B) Fig.…”

Section: Discussionmentioning

confidence: 99%

Expressions of Sox9, Sox5, and Sox13 transcription factors in mice testis during postnatal development

2015

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SRY-related box (Sox) transcription factors are conserved among vertebrate species. These proteins regulate multiple processes including sex determination and testis differentiation of the male embryo. Although members of the Sox family have been identified in pre- and postnatal Sertoli cells, they have never been characterized in adult Leydig cells. The objectives of this research were to identify expressions of Sox9, Sox5, and Sox13 in mice Leydig cell cultures and to establish their expression profiles in postnatal mice testes at different developmental stages. Methods used include Western blots and qPCR of stimulated MA-10 cell cultures and whole mice testes. Sox9, Sox5, and Sox13 proteins were detected in MA-10 cells as well as whole mouse testis. Although Sox9, Sox5, and Sox13 mRNA levels from whole mice testes tended to increase according to postnatal development, these results were not significant. Sox members were also detected in whole mice testis by Western Blot. However, Sox9, Sox5, and Sox13 protein expressions remained relatively constant during postnatal development from postnatal (P) day 60 to P365. Being newly characterized in the mouse testis, Sox13 was mainly localized by immunofluorescence within the nuclei of cells from seminiferous tubules, possibly spermatocytes and Sertoli cells. In addition, Sox9, Sox5, and Sox13 proteins were characterized in the nuclei of MA-10 Leydig cell cultures. Their expressions and transcriptional activities remained unaffected by activators of the cAMP/PKA pathway. Thus, Sox9, Sox5, and Sox13 transcription factors are expressed in postnatal testis and may regulate multiple functions such as steroidogenesis and spermatogenesis.

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“…It seems likely that in rat testes b-catenin serves as an important member of the cell adhesion complex rather than a transcriptional regulator of the Wnt signaling pathway. On the other hand, Kerr et al (2014) have recently detected nuclear b-catenin in murine spermatocytes and spermatids and based on mouse model with b-catenin mutation (AhCre Ctnnb1 fl/fl ) proposed Wnt/b-catenin signaling as required at several stages of spermatogenesis. It should be added that other authors also reported that deletion of b-catenin gene or its stabilizing mutation in germ cells caused germ cell deficiency and spermatogenic failure (Kimura et al, 2006;Chang et al, 2011).…”

Section: (A) (B)mentioning

confidence: 99%

“…It has been shown that perturbation of b-catenin signaling in embryonic testis caused testicular degeneration, Mullerian duct regression and testis maldescent (Chang et al, 2008;Tanwar et al, 2010;Kobayashi et al, 2011). Recently, involvement of Wnt/b-catenin signaling in spermatogenesis has also been explored (Kerr et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Flutamide alters the distribution of c-Src and affects the N-cadherin-β-catenin complex in the seminiferous epithelium of adult rat

et al. 2015

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Flutamide alters the distribution of c-Src and affects the N-cadherinb-catenin complex in the seminiferous epithelium of adult rat SUMMARYThis study was undertaken to explore interactions between c-Src kinase and the N-cadherin-b-catenin complex in seminiferous tubules of flutamide-treated rats. An anti-androgen flutamide (50 mg/kg bw) was injected daily into adult rats from postnatal days 82 to 88. Testes from 90-day-old control and flutamide-treated rats were used for experiments. Flutamide did not affect testis morphology, but impaired connexin43 immunoexpression between Sertoli cells at the blood-testis barrier (BTB) region, indicating the BTB as a sensitive target for flutamide. Real-time RT-PCR and western blot analyses revealed upregulation of N-cadherin at the mRNA and protein level after flutamide exposure (p < 0.05), whereas no changes in b-catenin and c-Src expression were observed. Notably, membranous b-catenin immunolocalization indicated its involvement in the cell adhesion complex rather than its contribution to the Wnt signaling pathway. As we used an exposure regime which avoided germ cell loss, it is likely that changes in the N-cadherin-b-catenin complex are a primary effect of androgen signaling disruption by flutamide. Immunohistochemistry revealed a diffusion of N-cadherin and b-catenin signals away from the BTB with concomitant disruption of c-Src staining pattern. As detected by immunofluorescence and coimmunoprecipitation, flutamide promoted disassembly of the N-cadherin-ß-catenin complex, induced N-cadherin to dissociate from c-Src at the BTB site, and altered interactions between the cell junction proteins and/or c-Src. Equally important, increased levels of p-N-cadherin-Tyr860 and p-b-catenin-Tyr654 (p < 0.05) pointed to a mechanism related to adhesion complex disassembly and suggested a potential role of c-Src in the control of the protein-protein dynamics. Overall, for the first time we have shown that flutamide alters the distribution of c-Src and affects N-cadherin-b-catenin interactions at the BTB. Understanding mechanism(s) by which anti-androgens can affect intercellular adhesion within the testis is relevant for predicting and preventing reproductive disorders affecting male fertility.

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Regulated Wnt/Beta-Catenin Signaling Sustains Adult Spermatogenesis in Mice1

Cited by 72 publications

References 45 publications

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

Expressions of Sox9, Sox5, and Sox13 transcription factors in mice testis during postnatal development

Flutamide alters the distribution of c-Src and affects the N-cadherin-β-catenin complex in the seminiferous epithelium of adult rat

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