Journal
STEM CELLS
Volume 31, Issue 11, Pages 2517-2527Publisher
WILEY
DOI: 10.1002/stem.1486
Keywords
Germline; Tissue-specific stem cells; Stem cell-microenvironment interactions; MAPK
Categories
Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI Grant [21227008]
- Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) KAKENHI [23116710]
- NIH [GM098605]
- JSPS
- Transdisciplinary Research Integration Center of the Research Organization of Information and Systems
- Grants-in-Aid for Scientific Research [21227008] Funding Source: KAKEN
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Coordination of stem cell fate is regulated by extrinsic niche signals and stem cell intrinsic factors. In mammalian testes, spermatogonial stem cells maintain constant production of abundant spermatozoa by alternating between self-renewal and differentiation at regular intervals according to a periodical program known as the seminiferous epithelial cycle. Although retinoic acid (RA) signaling has been suggested to direct the cyclical differentiation of spermatogonial stem cells, it remains largely unclear how their cycle-dependent self-renewal/proliferation is regulated. Here, we show that MEK/ERK signaling contributes to the cyclical activity of spermatogonial stem cells. We found that ERK1/2 is periodically activated in Sertoli cells during the stem cell self-renewal/proliferation phase, and that MEK/ERK signaling is required for the stage-related expression of the critical niche factor GDNF. In addition, ERK1/2 is activated in GFR1-positive spermatogonial stem cells under the control of GDNF and prevent them from being differentiated. These results suggest that MEK/ERK signaling directly and indirectly maintains spermatogonial stem cells by mediating a signal that promotes their periodical self-renewal/proliferation. Conversely, RA signaling directly and indirectly induces differentiation of spermatogonial stem cells. We propose that temporally regulated activations of RA signaling and a signal regulating MEK/ERK antagonistically coordinates the cycle-related activity of spermatogonial stem cells. Stem Cells2013;31:2517-2527
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