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Science 25 February 2000:
Vol. 287. no. 5457, pp. 1489 - 1493
DOI: 10.1126/science.287.5457.1489
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Reports

Regulation of Cell Fate Decision of Undifferentiated Spermatogonia by GDNF

Xiaojuan Meng, 1 Maria Lindahl, 2* Mervi E. Hyvönen, 1* Martti Parvinen, 5 Dirk G. de Rooij, 6 Michael W. Hess, 3 Anne Raatikainen-Ahokas, 1 Kirsi Sainio, 1 Heikki Rauvala, 4 Merja Lakso, 4 José G. Pichel, 7 Heiner Westphal, 8 Mart Saarma, 2 Hannu Sariola 1dagger

The molecular control of self-renewal and differentiation of stem cells has remained enigmatic. Transgenic loss-of-function and overexpression models now show that the dosage of glial cell line-derived neurotrophic factor (GDNF), produced by Sertoli cells, regulates cell fate decisions of undifferentiated spermatogonial cells that include the stem cells for spermatogenesis. Gene-targeted mice with one GDNF-null allele show depletion of stem cell reserves, whereas mice overexpressing GDNF show accumulation of undifferentiated spermatogonia. They are unable to respond properly to differentiation signals and undergo apoptosis upon retinoic acid treatment. Nonmetastatic testicular tumors are regularly formed in older GDNF-overexpressing mice. Thus, GDNF contributes to paracrine regulation of spermatogonial self-renewal and differentiation.

1 Research Programs of Developmental Biology,
2 Molecular Neurobiology,
3 Electron Microscopy Unit, Institute of Biotechnology, Viikki Biocenter, Post Office Box 56 (Street address: Viikinkaari 9),
4 Transgenic Unit, Institute of Biotechnology and Department of Biosciences, Post Office Box 56, FIN-00014 University of Helsinki, Finland.
5 Department of Anatomy, University of Turku, FIN-20520 Turku, Finland.
6 Department of Cell Biology, University Medical Center Utrecht, AZU-RM G02.525, Heidelberglaan 100, 3584 CX Utrecht, Netherlands.
7 Unidad de Investigación, Hospital de Mérida, Polígono Nueva Ciudad s/n, 06800 Mérida, Badajoz, Spain.
8 National Institute of Child Health and Human Development, Building 6B, Room 413, Bethesda, MD 20892-2790, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: hannu.sariola{at}helsinki.fi

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Spermatogonial Depletion in Adult Pin1-Deficient Mice.
F. W. Atchison and A. R. Means (2003)
Biol Reprod 69, 1989-1997
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Morphological Characterization of the Spermatogonial Subtypes in the Neonatal Mouse Testis.
L. Dettin, N. Ravindranath, M.-C. Hofmann, and M. Dym (2003)
Biol Reprod 69, 1565-1571
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Novel functions and signalling pathways for GDNF.
H. Sariola and M. Saarma (2003)
J. Cell Sci. 116, 3855-3862
   Abstract »    Full Text »    PDF »
Dramatic Expansion of Germinal Stem Cells by Ectopically Expressed Human Glial Cell Line-Derived Neurotrophic Factor in Mouse Sertoli Cells.
K. Yomogida, Y. Yagura, Y. Tadokoro, and Y. Nishimune (2003)
Biol Reprod 69, 1303-1307
   Abstract »    Full Text »    PDF »
Developmental expression of BMP4/ALK3/SMAD5 signaling pathway in the mouse testis: a potential role of BMP4 in spermatogonia differentiation.
M. Pellegrini, P. Grimaldi, P. Rossi, R. Geremia, and S. Dolci (2003)
J. Cell Sci. 116, 3363-3372
   Abstract »    Full Text »    PDF »
Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line.
A. Goriely, G. A. T. McVean, M. Rojmyr, B. Ingemarsson, and A. O. M. Wilkie (2003)
Science 301, 643-646
   Abstract »    Full Text »    PDF »
Long-Term Proliferation in Culture and Germline Transmission of Mouse Male Germline Stem Cells.
M. Kanatsu-Shinohara, N. Ogonuki, K. Inoue, H. Miki, A. Ogura, S. Toyokuni, and T. Shinohara (2003)
Biol Reprod 69, 612-616
   Abstract »    Full Text »    PDF »
Maintenance of Mouse Male Germ Line Stem Cells In Vitro.
M. Nagano, B.-Y. Ryu, C. J. Brinster, M. R. Avarbock, and R. L. Brinster (2003)
Biol Reprod 68, 2207-2214
   Abstract »    Full Text »    PDF »
Increment of Murine Spermatogonial Cell Number by Gonadotropin-Releasing Hormone Analogue Is Independent of Stem Cell Factor c-kit Signal.
M. Ohmura, T. Ogawa, M. Ono, M. Dezawa, M. Hosaka, Y. Kubota, and H. Sawada (2003)
Biol Reprod 68, 2304-2313
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Cell Cycle Regulation in Retinal Progenitors by Glia-Derived Neurotrophic Factor and Docosahexaenoic Acid.
M. F. Insua, A. Garelli, N. P. Rotstein, O. L. German, A. Arias, and L. E. Politi (2003)
Invest. Ophthalmol. Vis. Sci. 44, 2235-2244
   Abstract »    Full Text »    PDF »
Testis Morphometry, Seminiferous Epithelium Cycle Length, and Daily Sperm Production in Domestic Cats (Felis catus).
L. R. Franca and C. L. Godinho (2003)
Biol Reprod 68, 1554-1561
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