Stem Cell Defects in ATM-Deficient Undifferentiated Spermatogonia through DNA Damage-Induced Cell-Cycle Arrest

Keiyo Takubo, Masako Ohmura, Masaki Azuma, Go Nagamatsu, Wakako Yamasawa, Fumio Arai, Atsushi Hirao, Toshio Suda

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Mammalian spermatogenesis is maintained by stem cell capacity within undifferentiated spermatogonial subpopulation. Here, using a combination of surface markers, we describe a purification method for undifferentiated spermatogonia. Flow cytometric analysis revealed that this population is composed of Plzf-positive cells and exhibits quiescence and the side population phenotype, fulfilling general stem cell criteria. We then applied this method to analyze undifferentiated spermatogonia and stem cell activity of Atm-/- mice. Atm-/- testis shows progressive depletion of undifferentiated spermatogonia accompanied by cell-cycle arrest. In Atm-/- undifferentiated spermatogonia, a self-renewal defect was observed in vitro and in vivo. Accumulation of DNA damage and activation of the p19Arf-p53-p21Cip1/Waf1 pathway were observed in Atm-/- undifferentiated spermatogonia. Moreover, suppression of p21Cip1/Waf1 in an Atm-/- background restored transplantation ability of undifferentiated spermatogonia, indicating that ATM plays an essential role in maintenance of undifferentiated spermatogonia and their stem cell capacity by suppressing DNA damage-induced cell-cycle arrest.

Original languageEnglish
Pages (from-to)170-182
Number of pages13
JournalCell Stem Cell
Volume2
Issue number2
DOIs
Publication statusPublished - 2008 Feb 7

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Spermatogonia
Cell Cycle Checkpoints
DNA Damage
Stem Cells
Spermatogenesis
Population
Testis
Transplantation
Maintenance
Phenotype

Keywords

  • STEMCELL

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

Cite this

Stem Cell Defects in ATM-Deficient Undifferentiated Spermatogonia through DNA Damage-Induced Cell-Cycle Arrest. / Takubo, Keiyo; Ohmura, Masako; Azuma, Masaki; Nagamatsu, Go; Yamasawa, Wakako; Arai, Fumio; Hirao, Atsushi; Suda, Toshio.

In: Cell Stem Cell, Vol. 2, No. 2, 07.02.2008, p. 170-182.

Research output: Contribution to journalArticle

Takubo, Keiyo ; Ohmura, Masako ; Azuma, Masaki ; Nagamatsu, Go ; Yamasawa, Wakako ; Arai, Fumio ; Hirao, Atsushi ; Suda, Toshio. / Stem Cell Defects in ATM-Deficient Undifferentiated Spermatogonia through DNA Damage-Induced Cell-Cycle Arrest. In: Cell Stem Cell. 2008 ; Vol. 2, No. 2. pp. 170-182.
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