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First published online 11 April 2007
doi: 10.1242/dev.003004
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1 Department of Molecular Genetics, Graduate School of Medicine, Kyoto
University, Kyoto 606-8501, Japan.
2 Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto
University, Kyoto 606-8501, Japan.
3 The Institute of Physical and Chemical Research (RIKEN), Bioresource Center,
Ibaraki 305-0074, Japan.
4 Department of Pathology and Biology of Diseases, Graduate School of Medicine,
Kyoto University, Kyoto 606-8501, Japan.
5 Department of Pathology, Graduate School of Medicine, Osaka University, Suita,
Osaka 565-0871, Japan.
* Author for correspondence (e-mail: tshinoha{at}virus.kyoto-u.ac.jp)
Accepted 13 March 2007
Spermatogonial stem cells have unique properties to self-renew and support spermatogenesis throughout their lifespan. Although glial cell line-derived neurotrophic factor (GDNF) has recently been identified as a self-renewal factor for spermatogonial stem cells, the molecular mechanism of spermatogonial stem cell self-renewal remains unclear. In the present study, we assessed the role of the phosphoinositide-3 kinase (PI3K)-Akt pathway using a germline stem (GS) cell culture system that allows in vitro expansion of spermatogonial stem cells. Akt was rapidly phosphorylated when GDNF was added to the GS cell culture, and the addition of a chemical inhibitor of PI3K prevented GS cell self-renewal. Furthermore, conditional activation of the myristoylated form of Akt-Mer (myr-Akt-Mer) by 4-hydroxy-tamoxifen induced logarithmic proliferation of GS cells in the absence of GDNF for at least 5 months. The myr-Akt-Mer GS cells expressed spermatogonial markers and retained androgenetic imprinting patterns. In addition, they supported spermatogenesis and generated offspring following spermatogonial transplantation into the testes of infertile recipient mice, indicating that they are functionally normal. These results demonstrate that activation of the PI3K-Akt pathway plays a central role in the self-renewal division of spermatogonial stem cells.
Key words: Spermatogenesis, Testis, Stem cells, Transplantation, Microinsemination, Mouse
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