Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice.
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 mo...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0251911 |
| _version_ | 1819180768713244672 |
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| author | Alexandre Boyer Xiangfan Zhang Adrien Levasseur Nour Abou Nader Guillaume St-Jean Makoto C Nagano Derek Boerboom |
| author_facet | Alexandre Boyer Xiangfan Zhang Adrien Levasseur Nour Abou Nader Guillaume St-Jean Makoto C Nagano Derek Boerboom |
| author_sort | Alexandre Boyer |
| collection | DOAJ |
| description | 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 Ctnnb1tm1Mmt/+; Ddx4-CreTr/+ (ΔCtnnb1) mouse model, in which a stabilized form of CTNNB1 is expressed in all germ cells. ΔCtnnb1 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 ΔCtnnb1 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. |
| first_indexed | 2024-12-22T22:19:36Z |
| format | Article |
| id | doaj.art-a5f945d92d5a42648ae0be699017d386 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T22:19:36Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a5f945d92d5a42648ae0be699017d3862022-12-21T18:10:42ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01165e025191110.1371/journal.pone.0251911Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice.Alexandre BoyerXiangfan ZhangAdrien LevasseurNour Abou NaderGuillaume St-JeanMakoto C NaganoDerek BoerboomSpermatogenesis 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 Ctnnb1tm1Mmt/+; Ddx4-CreTr/+ (ΔCtnnb1) mouse model, in which a stabilized form of CTNNB1 is expressed in all germ cells. ΔCtnnb1 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 ΔCtnnb1 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.https://doi.org/10.1371/journal.pone.0251911 |
| spellingShingle | Alexandre Boyer Xiangfan Zhang Adrien Levasseur Nour Abou Nader Guillaume St-Jean Makoto C Nagano Derek Boerboom Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. PLoS ONE |
| title | Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. |
| title_full | Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. |
| title_fullStr | Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. |
| title_full_unstemmed | Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. |
| title_short | Constitutive activation of CTNNB1 results in a loss of spermatogonial stem cell activity in mice. |
| title_sort | constitutive activation of ctnnb1 results in a loss of spermatogonial stem cell activity in mice |
| url | https://doi.org/10.1371/journal.pone.0251911 |
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