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Tissue-Specific Stem Cells
Version of Record online: 18 JAN 2012
Copyright © 2011 AlphaMed Press
Volume 30, Issue 2, pages 280–291, February 2012
How to Cite
Sada, A., Hasegawa, K., Pin, P. H. and Saga, Y. (2012), NANOS2 Acts Downstream of Glial Cell Line-Derived Neurotrophic Factor Signaling to Suppress Differentiation of Spermatogonial Stem Cells. STEM CELLS, 30: 280–291. doi: 10.1002/stem.790
Author contributions: A.S.: conception and design, data analysis and interpretation, collection and assembly of data, and manuscript writing; K.H.: collection and assembly of data, data analysis and interpretation, and manuscript writing; P.H.P.: collection and assembly of data and manuscript writing; Y.S.: conception and design, manuscript writing, and financial support.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS November 18, 2011.
- Issue online: 18 JAN 2012
- Version of Record online: 18 JAN 2012
- Accepted manuscript online: 18 NOV 2011 04:48PM EST
- Manuscript Accepted: 9 NOV 2011
- Manuscript Received: 4 APR 2011
- Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (Japan)
- Japan Society for the Promotion of Science
- Tissue-specific stem cells;
- Targeted gene disruption;
- Transgenic mouse;
- Stem cell–microenvironment interactions
Stem cells are maintained by both stem cell-extrinsic niche signals and stem cell-intrinsic factors. During murine spermatogenesis, glial cell line-derived neurotrophic factor (GDNF) signal emanated from Sertoli cells and germ cell-intrinsic factor NANOS2 represent key regulators for the maintenance of spermatogonial stem cells. However, it remains unclear how these factors intersect in stem cells to control their cellular state. Here, we show that GDNF signaling is essential to maintain NANOS2 expression, and overexpression of Nanos2 can alleviate the stem cell loss phenotype caused by the depletion of Gfra1, a receptor for GDNF. By using an inducible Cre-loxP system, we show that NANOS2 expression is downregulated upon the conditional knockout (cKO) of Gfra1, while ectopic expression of Nanos2 in GFRA1-negative spermatogonia does not induce de novo GFRA1 expression. Furthermore, overexpression of Nanos2 in the Gfra1-cKO testes prevents precocious differentiation of the Gfra1-knockout stem cells and partially rescues the stem cell loss phenotypes of Gfra1-deficient mice, indicating that the stem cell differentiation can be suppressed by NANOS2 even in the absence of GDNF signaling. Taken together, we suggest that NANOS2 acts downstream of GDNF signaling to maintain undifferentiated state of spermatogonial stem cells. STEM CELLS 2012; 30:280–291.