Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Cycle
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Cell Differentiation / drug effects
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Cobalt / metabolism
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Drosophila Proteins*
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Female
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Gene Expression
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Gene Targeting
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Male
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Mice
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Mice, Transgenic
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Mitosis
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Nerve Growth Factors*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Sertoli Cells / cytology
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Sertoli Cells / physiology
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Spermatogenesis*
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Spermatogonia / cytology*
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Spermatogonia / drug effects
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Stem Cells / cytology*
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Testicular Neoplasms / pathology
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Testis / anatomy & histology
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Vitamin A / pharmacology
Substances
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Drosophila Proteins
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Gdnf protein, mouse
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Glial Cell Line-Derived Neurotrophic Factor
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Glial Cell Line-Derived Neurotrophic Factor Receptors
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Nerve Growth Factors
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Vitamin A
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cobalt ammonium complex
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Cobalt
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila