CDK2 kinase activity is a regulator of male germ cell fate
(2019) In Development (Cambridge) 146(21).- Abstract
The ability of men to remain fertile throughout their lives depends upon establishment of a spermatogonial stem cell (SSC) pool from gonocyte progenitors, and thereafter balancing SSC renewal vs terminal differentiation. Here, we report that precise regulation of the cell cycle is crucial for this balance. Whereas cyclin-dependent kinase 2 (Cdk2) is unnecessary for mouse viability or gametogenesis stages prior to meiotic prophase I, mice bearing a deregulated allele (Cdk2
Y15S
) are severely deficient in spermatogonial differentiation. This allele disrupts an inhibitory phosphorylation site (Tyr15) for the kinase WEE1. Remarkably, Cdk2
Y15S/Y15S
mice possess abnormal clusters of mitotically active SSC-like cells, but... (More)The ability of men to remain fertile throughout their lives depends upon establishment of a spermatogonial stem cell (SSC) pool from gonocyte progenitors, and thereafter balancing SSC renewal vs terminal differentiation. Here, we report that precise regulation of the cell cycle is crucial for this balance. Whereas cyclin-dependent kinase 2 (Cdk2) is unnecessary for mouse viability or gametogenesis stages prior to meiotic prophase I, mice bearing a deregulated allele (Cdk2
(Less)
Y15S
) are severely deficient in spermatogonial differentiation. This allele disrupts an inhibitory phosphorylation site (Tyr15) for the kinase WEE1. Remarkably, Cdk2
Y15S/Y15S
mice possess abnormal clusters of mitotically active SSC-like cells, but they are eventually removed by apoptosis after failing to differentiate properly. Analyses of lineage markers, germ cell proliferation over time, and single cell RNA-seq data revealed delayed and defective differentiation of gonocytes into SSCs. Biochemical and genetic data demonstrated that Cdk2
Y15S
is a gain-of-function allele causing elevated kinase activity, which underlies these differentiation defects. Our results demonstrate that precise regulation of CDK2 kinase activity in male germ cell development is critical for the gonocyte-to-spermatogonial transition and long-term spermatogenic homeostasis.
- author
- Singh, Priti ; Patel, Ravi K ; Palmer, Nathan ; Grenier, Jennifer K ; Paduch, Darius ; Kaldis, Philipp LU ; Grimson, Andrew and Schimenti, John C
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- in
- Development (Cambridge)
- volume
- 146
- issue
- 21
- article number
- dev180273
- publisher
- The Company of Biologists Ltd
- external identifiers
-
- scopus:85074203366
- pmid:31582414
- ISSN
- 1477-9129
- DOI
- 10.1242/dev.180273
- language
- English
- LU publication?
- no
- id
- 6d015161-2c7f-4e83-9841-b65c90387d57
- date added to LUP
- 2019-10-09 18:36:52
- date last changed
- 2024-04-30 22:37:54
@article{6d015161-2c7f-4e83-9841-b65c90387d57, abstract = {{<p>The ability of men to remain fertile throughout their lives depends upon establishment of a spermatogonial stem cell (SSC) pool from gonocyte progenitors, and thereafter balancing SSC renewal vs terminal differentiation. Here, we report that precise regulation of the cell cycle is crucial for this balance. Whereas cyclin-dependent kinase 2 (Cdk2) is unnecessary for mouse viability or gametogenesis stages prior to meiotic prophase I, mice bearing a deregulated allele (Cdk2<br> Y15S<br> ) are severely deficient in spermatogonial differentiation. This allele disrupts an inhibitory phosphorylation site (Tyr15) for the kinase WEE1. Remarkably, Cdk2<br> Y15S/Y15S<br> mice possess abnormal clusters of mitotically active SSC-like cells, but they are eventually removed by apoptosis after failing to differentiate properly. Analyses of lineage markers, germ cell proliferation over time, and single cell RNA-seq data revealed delayed and defective differentiation of gonocytes into SSCs. Biochemical and genetic data demonstrated that Cdk2<br> Y15S<br> is a gain-of-function allele causing elevated kinase activity, which underlies these differentiation defects. Our results demonstrate that precise regulation of CDK2 kinase activity in male germ cell development is critical for the gonocyte-to-spermatogonial transition and long-term spermatogenic homeostasis.</p>}}, author = {{Singh, Priti and Patel, Ravi K and Palmer, Nathan and Grenier, Jennifer K and Paduch, Darius and Kaldis, Philipp and Grimson, Andrew and Schimenti, John C}}, issn = {{1477-9129}}, language = {{eng}}, number = {{21}}, publisher = {{The Company of Biologists Ltd}}, series = {{Development (Cambridge)}}, title = {{CDK2 kinase activity is a regulator of male germ cell fate}}, url = {{http://dx.doi.org/10.1242/dev.180273}}, doi = {{10.1242/dev.180273}}, volume = {{146}}, year = {{2019}}, }