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CDK2 kinase activity is a regulator of male germ cell fate

Singh, Priti ; Patel, Ravi K ; Palmer, Nathan ; Grenier, Jennifer K ; Paduch, Darius ; Kaldis, Philipp LU orcid ; Grimson, Andrew and Schimenti, John C (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
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.

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author
; ; ; ; ; ; and
publishing date
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
  • pmid:31582414
  • scopus:85074203366
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}},
}