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TISSUE-SPECIFIC STEM CELLS

Gdnf Upregulates c-Fos Transcription via the Ras/Erk1/2 Pathway to Promote Mouse Spermatogonial Stem Cell Proliferation

^aDepartment of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, District of Columbia, USA;
^bDepartment of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois, USA

Key Words. GDNF • Spermatogonial stem cells • Ret • Ras/ERK pathway • CREB/ATF-1 family • c-fos

Correspondence: Correspondence: Martin Dym, Ph.D., Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC, 20057, USA. Telephone: 202-687-1184; Fax: 202-687-8218; e-mail: dymm{at}georgetown.edu

Received on June 21, 2007; accepted for publication on October 15, 2007.

First published online in STEM CELLS EXPRESS  October 25, 2007.


Glial cell line-derived neurotrophic factor (GDNF) plays a crucial role in regulating the proliferation of spermatogonial stem cells (SSC). The signaling pathways mediating the function of GDNF in SSC remain unclear. This study was designed to determine whether GDNF signals via the Ras/ERK1/2 pathway in the C18-4 cells, a mouse SSC line. The identity of this cell line was confirmed by the expression of various markers for germ cells, proliferating spermatogonia, and SSC, including GCNA1, Vasa, Dazl, PCNA, Oct-4, GFR1, Ret, and Plzf. Western blot analysis revealed that GDNF activated Ret tyrosine phosphorylation. All 3 isoforms of Shc were phosphorylated upon GDNF stimulation, and GDNF induced the binding of the phosphorylated Ret to Shc and Grb2 as indicated by immunoprecipitation and Western blotting. The active Ras was induced by GDNF, which further activated ERK1/2 phosphorylation. GDNF stimulated the phosphorylation of CREB-1, ATF-1, and CREM-1, and c-fos transcription. Notably, the increase in ERK1/2 phosphorylation, c-fos transcription, bromodeoxyuridine incorporation, and metaphase counts induced by GDNF, was completely blocked by pretreatment with PD98059, a specific inhibitor for MEK1, the upstream regulator of ERK1/2. GDNF stimulation eventually upregulated cyclin A and CDK2 expression. Together, these data suggest that GDNF induces CREB/ATF-1 family member phosphorylation and c-fos transcription via the Ras/ERK1/2 pathway to promote the proliferation of SSC. Unveiling GDNF signaling cascades in SSC has important implications in providing attractive targets for male contraception as well as for the regulation of stem cell renewal vs. differentiation.

Disclosure of potential conflicts of interest is found at the end of this article.

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