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Genes Dev. 2015 Dec 1;29(23):2420-34. doi: 10.1101/gad.271783.115. Epub 2015 Nov 19.

High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells.

Author information

1
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA;
2
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Genetics, Stanford University, California 94305, USA;
3
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
4
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh Pennsylvania 15213, USA; Magee-Womens Research Institute, Pittsburgh, Pennsylvania 15213, USA;
5
Department of Genetics, Stanford University, California 94305, USA;
6
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA; Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA.

Abstract

Telomerase inactivation causes loss of the male germline in worms, fish, and mice, indicating a conserved dependence on telomere maintenance in this cell lineage. Here, using telomerase reverse transcriptase (Tert) reporter mice, we found that very high telomerase expression is a hallmark of undifferentiated spermatogonia, the mitotic population where germline stem cells reside. We exploited these high telomerase levels as a basis for purifying undifferentiated spermatogonia using fluorescence-activated cell sorting. Telomerase levels in undifferentiated spermatogonia and embryonic stem cells are comparable and much greater than in somatic progenitor compartments. Within the germline, we uncovered an unanticipated gradient of telomerase activity that also enables isolation of more mature populations. Transcriptomic comparisons of Tert(High) undifferentiated spermatogonia and Tert(Low) differentiated spermatogonia by RNA sequencing reveals marked differences in cell cycle and key molecular features of each compartment. Transplantation studies show that germline stem cell activity is confined to the Tert(High) cKit(-) population. Telomere shortening in telomerase knockout strains causes depletion of undifferentiated spermatogonia and eventual loss of all germ cells after undifferentiated spermatogonia drop below a critical threshold. These data reveal that high telomerase expression is a fundamental characteristic of germline stem cells, thus explaining the broad dependence on telomerase for germline immortality in metazoans.

KEYWORDS:

aging; germline stem cells; spermatogenesis; telomerase; telomeres

PMID:
26584619
PMCID:
PMC4691947
DOI:
10.1101/gad.271783.115
[Indexed for MEDLINE]
Free PMC Article

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