Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway

Mito Kanatsu-Shinohara; Honda Naoki; Takashi Tanaka; Misako Tatehana; Takako Kikkawa; Noriko Osumi; Takashi Shinohara

doi:10.1016/j.stemcr.2022.07.007

Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway

Mito Kanatsu-Shinohara, Honda Naoki, Takashi Tanaka, Misako Tatehana, Takako Kikkawa, Noriko Osumi, Takashi Shinohara

Research output: Contribution to journal › Article › peer-review

Abstract

A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT⁺ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.

Original language	English
Pages (from-to)	1924-1941
Number of pages	18
Journal	Stem Cell Reports
Volume	17
Issue number	9
DOIs	https://doi.org/10.1016/j.stemcr.2022.07.007
Publication status	Published - 2022 Sept 13
Externally published	Yes

Keywords

Cdkn1a
Trp53
apoptosis
spermatogenesis

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2022.07.007

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title = "Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway",

abstract = "A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.",

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author = "Mito Kanatsu-Shinohara and Honda Naoki and Takashi Tanaka and Misako Tatehana and Takako Kikkawa and Noriko Osumi and Takashi Shinohara",

note = "Funding Information: We thank Dr. Kana Yoshido for statistical analysis. Financial support for this research was provided by The Uehara Memorial Foundation , AMED ( 17933225 and JP21gm1110008 ), and MEXT ( 19K22512 , 19H05750 , 19H04906 , 18H04882 , 18H05281 , and 18H02935 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

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AU - Kanatsu-Shinohara, Mito

AU - Naoki, Honda

AU - Tanaka, Takashi

AU - Tatehana, Misako

AU - Kikkawa, Takako

AU - Osumi, Noriko

AU - Shinohara, Takashi

N1 - Funding Information: We thank Dr. Kana Yoshido for statistical analysis. Financial support for this research was provided by The Uehara Memorial Foundation , AMED ( 17933225 and JP21gm1110008 ), and MEXT ( 19K22512 , 19H05750 , 19H04906 , 18H04882 , 18H05281 , and 18H02935 ). Publisher Copyright: © 2022 The Author(s)

PY - 2022/9/13

Y1 - 2022/9/13

N2 - A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.

AB - A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.

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KW - spermatogenesis

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Regulation of male germline transmission patterns by the Trp53-Cdkn1a pathway

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