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

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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. © 2008 Elsevier Inc. All rights reserved.

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Takubo, K., Ohmura, M., Azuma, M., Nagamatsu, G., Yamada, W., Arai, F., … Suda, T. (2008). Stem Cell Defects in ATM-Deficient Undifferentiated Spermatogonia through DNA Damage-Induced Cell-Cycle Arrest. Cell Stem Cell, 2(2), 170–182. https://doi.org/10.1016/j.stem.2007.10.023

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