☆ 4.6 Article

Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice

PLOS ONE (2021)

Journal

PLOS ONE

Volume 16, Issue 5, Pages -

Publisher

PUBLIC LIBRARY SCIENCE

DOI: 10.1371/journal.pone.0251911

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Funding

Natural Sciences and Engineering Research Council of Canada [RGPIN-03745, RGPIN-04358, RGPIN-05230]
Canadian Institutes of Health Research [MOP130467, PJT156305, PJT153233]

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Abstract

In spermatogenesis, CTNNB1 signaling promotes the transition of spermatogonial stem cells to undifferentiated progenitor spermatogonia at the expense of their self-renewal.

Spermatogenesis requires that a careful balance be maintained between the self-renewal of spermatogonial stem cells (SSCs) and their commitment to the developmental pathway through which they will differentiate into spermatozoa. Recently, a series of studies employing various in vivo and in vitro models have suggested a role of the wingless-related MMTV integration site gene family/beta-catenin (WNT/CTNNB1) pathway in determining the fate of SSCs. However, conflicting data have suggested that CTNNB1 signaling may either promote SSC self-renewal or differentiation. Here, we studied the effects of sustained CTNNB1 signaling in SSCs using the Ctnnb1(tm1Mmt/+); Ddx4-Cre(Tr/+) (Delta Ctnnb1) mouse model, in which a stabilized form of CTNNB1 is expressed in all germ cells. Delta Ctnnb1 mice were found to have reduced testis weights and partial germ cell loss by 4 months of age. Germ cell transplantation assays showed a 49% reduction in total functional SSC numbers in 8 month-old transgenic mice. In vitro, Thy1-positive undifferentiated spermatogonia from Delta Ctnnb1 mice formed 57% fewer clusters, which was associated with decreased cell proliferation. A reduction in mRNA levels of genes associated with SSC maintenance (Bcl6b, Gfra1, Plzf) and increased levels for markers associated with progenitor and differentiating spermatogonia (Kit, Rarg, Sohlh1) were detected in these cluster cells. Furthermore, RNAseq performed on these clusters revealed a network of more than 900 genes regulated by CTNNB1, indicating that CTNNB1 is an important regulator of spermatogonial fate. Together, our data support the notion that CTNNB1 signaling promotes the transition of SSCs to undifferentiated progenitor spermatogonia at the expense of their self-renewal.

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Spermatogonial fate in mice with increased activin A bioactivity and testicular somatic cell tumours

Penny A. F. Whiley, Benedict Nathaniel, Peter G. Stanton, Robin M. Hobbs, Kate L. Loveland

Summary: Adult male fertility depends on spermatogonial stem cells (SSCs) which undergo self-renewal or differentiation in response to microenvironmental signals. This study reveals that chronically elevated activin A affects SSC fate in vivo and suggests that it promotes a microenvironment supporting SSC self-renewal. Testis stromal tumours in Inha KO mice create a microenvironment that supports SSC self-renewal, offering a potential strategy for improving spermatogonial propagation in vitro.

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