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

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2007 Oct 27

PMID 17962702

Citations 127

Authors

Zuping He

Jiji Jiang

Maria Kokkinaki

Nady Golestaneh

Marie-Claude Hofmann

Martin Dym

Affiliations

Soon will be listed here.

Abstract

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, GFRalpha1, 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.

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References

Blendy J, Kaestner K, Schmid W, Gass P, Schutz G . Targeting of the CREB gene leads to up-regulation of a novel CREB mRNA isoform. EMBO J. 1996; 15(5):1098-106. PMC: 450007. View

Kubota H, Avarbock M, Brinster R . Growth factors essential for self-renewal and expansion of mouse spermatogonial stem cells. Proc Natl Acad Sci U S A. 2004; 101(47):16489-94. PMC: 534530. DOI: 10.1073/pnas.0407063101. View

Giuili G, Tomljenovic A, Labrecque N, Oulad-Abdelghani M, Rassoulzadegan M, Cuzin F . Murine spermatogonial stem cells: targeted transgene expression and purification in an active state. EMBO Rep. 2002; 3(8):753-9. PMC: 1084203. DOI: 10.1093/embo-reports/kvf149. View

Yoon S, Seger R . The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006; 24(1):21-44. DOI: 10.1080/02699050500284218. View

Brinster R . Germline stem cell transplantation and transgenesis. Science. 2002; 296(5576):2174-6. PMC: 4881847. DOI: 10.1126/science.1071607. View

Lin L, Doherty D, Lile J, Bektesh S, Collins F . GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science. 1993; 260(5111):1130-2. DOI: 10.1126/science.8493557. View

Wittinghofer A . Signal transduction via Ras. Biol Chem. 1998; 379(8-9):933-7. View

Meng X, Lindahl M, Hyvonen M, Parvinen M, de Rooij D, Hess M . Regulation of cell fate decision of undifferentiated spermatogonia by GDNF. Science. 2000; 287(5457):1489-93. DOI: 10.1126/science.287.5457.1489. View

Prathapam T, Tegen S, Oskarsson T, Trumpp A, Martin G . Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition. Proc Natl Acad Sci U S A. 2006; 103(8):2695-700. PMC: 1413844. DOI: 10.1073/pnas.0511186103. View

10.

Blume-Jensen P, Jiang G, HYMAN R, Lee K, OGorman S, Hunter T . Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3'-kinase is essential for male fertility. Nat Genet. 2000; 24(2):157-62. DOI: 10.1038/72814. View

11.

Braydich-Stolle L, Kostereva N, Dym M, Hofmann M . Role of Src family kinases and N-Myc in spermatogonial stem cell proliferation. Dev Biol. 2007; 304(1):34-45. PMC: 2077853. DOI: 10.1016/j.ydbio.2006.12.013. View

12.

Golden J, DeMaro J, Osborne P, Milbrandt J, Johnson Jr E . Expression of neurturin, GDNF, and GDNF family-receptor mRNA in the developing and mature mouse. Exp Neurol. 1999; 158(2):504-28. DOI: 10.1006/exnr.1999.7127. View

13.

Arenas E, TRUPP M, Akerud P, Ibanez C . GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron. 1995; 15(6):1465-73. DOI: 10.1016/0896-6273(95)90024-1. View

14.

Fimia G, De Cesare D, Sassone-Corsi P . CBP-independent activation of CREM and CREB by the LIM-only protein ACT. Nature. 1999; 398(6723):165-9. DOI: 10.1038/18237. View

15.

Dolci S, Pellegrini M, Di Agostino S, Geremia R, Rossi P . Signaling through extracellular signal-regulated kinase is required for spermatogonial proliferative response to stem cell factor. J Biol Chem. 2001; 276(43):40225-33. DOI: 10.1074/jbc.M105143200. View

16.

Du H, Tang N, Liu B, You B, Shen F, Ye M . Benzo[a]pyrene-induced cell cycle progression is through ERKs/cyclin D1 pathway and requires the activation of JNKs and p38 mapk in human diploid lung fibroblasts. Mol Cell Biochem. 2006; 287(1-2):79-89. DOI: 10.1007/s11010-005-9073-7. View

17.

Ravnik S, Wolgemuth D . Regulation of meiosis during mammalian spermatogenesis: the A-type cyclins and their associated cyclin-dependent kinases are differentially expressed in the germ-cell lineage. Dev Biol. 1999; 207(2):408-18. DOI: 10.1006/dbio.1998.9156. View

18.

Hummler E, Cole T, Blendy J, Ganss R, Aguzzi A, Schmid W . Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc Natl Acad Sci U S A. 1994; 91(12):5647-51. PMC: 44053. DOI: 10.1073/pnas.91.12.5647. View

19.

Tadokoro Y, Yomogida K, Ohta H, Tohda A, Nishimune Y . Homeostatic regulation of germinal stem cell proliferation by the GDNF/FSH pathway. Mech Dev. 2002; 113(1):29-39. DOI: 10.1016/s0925-4773(02)00004-7. View

20.

Dym M . Spermatogonial stem cells of the testis. Proc Natl Acad Sci U S A. 1994; 91(24):11287-9. PMC: 45216. DOI: 10.1073/pnas.91.24.11287. View