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

  1. Steven E. Artandi1,2,6
  1. 1Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA;
  2. 2Cancer Biology Program, Stanford University School of Medicine, Stanford, California 94305, USA;
  3. 3Department of Genetics, Stanford University, California 94305, USA;
  4. 4Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh Pennsylvania 15213, USA;
  5. 5Magee-Womens Research Institute, Pittsburgh, Pennsylvania 15213, USA;
  6. 6Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA
  1. Corresponding author: sartandi{at}stanford.edu
  1. 7 These authors contributed equally to this work.

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 TertHigh undifferentiated spermatogonia and TertLow 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 TertHigh 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

Footnotes

  • Received September 11, 2015.
  • Accepted October 27, 2015.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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