Myc/Mycn-mediated glycolysis enhances mouse spermatogonial stem cell self-renewal

• Published in: Genes & development Vol. 30; no. 23; pp. 2637 - 2648
• Main Authors: Kanatsu-Shinohara, Mito, Tanaka, Takashi, Ogonuki, Narumi, Ogura, Atsuo, Morimoto, Hiroko, Cheng, Pei Feng, Eisenman, Robert N., Trumpp, Andreas, Shinohara, Takashi
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.12.2016
• Subjects: 3-Phosphoinositide-Dependent Protein Kinases - metabolism; Animals; Cell Division - genetics; Cell Proliferation - genetics; Cell Self Renewal - genetics; Gene Expression Regulation, Developmental - genetics; Gene Knockout Techniques; Glycolysis - genetics; Male; Mice; Mice, Inbred C57BL; N-Myc Proto-Oncogene Protein - genetics; N-Myc Proto-Oncogene Protein - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Research Paper; RNA Splicing Factors - metabolism; Spermatogonia - cytology; Stem Cells - enzymology; Stem Cells - metabolism; spermatogenesis; spermatogonial stem cells; self-renewal; Myc; glycolysis
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.287045.116

Myc plays critical roles in the self-renewal division of various stem cell types. In spermatogonial stem cells (SSCs), Myc controls SSC fate decisions because Myc overexpression induces enhanced self-renewal division, while depletion of Max , a Myc -binding partner, leads to meiotic induction. However, the mechanism by which Myc acts on SSC fate is unclear. Here we demonstrate a critical link between Myc/Mycn gene activity and glycolysis in SSC self-renewal. In SSCs, Myc/Mycn are regulated by Foxo1 , whose deficiency impairs SSC self-renewal. Myc/Mycn -deficient SSCs not only undergo limited self-renewal division but also display diminished glycolytic activity. While inhibition of glycolysis decreased SSC activity, chemical stimulation of glycolysis or transfection of active Akt1 or Pdpk1 (phosphoinositide-dependent protein kinase 1 ) augmented self-renewal division, and long-term SSC cultures were derived from a nonpermissive strain that showed limited self-renewal division. These results suggested that Myc -mediated glycolysis is an important factor that increases the frequency of SSC self-renewal division.