The In Vivo Response of Stem and Other Undifferentiated Spermatogonia to the Reversible Inhibition of Glial Cell Line-Derived Neurotrophic Factor Signaling in the Adult

Maintaining adequate numbers of spermatogonial stem cells is required for the production of the millions of sperm required for male fertility. To date, however, the mechanisms that regulate the size of this pool in the adult are poorly defined. Glial cell line‐derived neurotrophic factor (GDNF) is r...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2012-04, Vol.30 (4), p.732-740
Main Authors: Savitt, Joseph, Singh, Dolly, Zhang, Chao, Chen, Liang-Chin, Folmer, Janet, Shokat, Kevan M., Wright, William W.
Format: Article
Language:English
Subjects:
Aging - physiology
Amino Acid Substitution - genetics
Animals
Biomarkers - metabolism
Cell Differentiation
Glial cell line-derived neurotrophic factor
Glial Cell Line-Derived Neurotrophic Factor - metabolism
Male
Mice
Proto-Oncogene Proteins c-ret - metabolism
Ret
Sertoli cell
Signal Transduction
Spermatogenesis
Spermatogonia - cytology
Spermatogonia - metabolism
Stem Cells - cytology
Stem Cells - metabolism
Stem spermatogonia
Testis - cytology
Testis - metabolism
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Summary:Maintaining adequate numbers of spermatogonial stem cells is required for the production of the millions of sperm required for male fertility. To date, however, the mechanisms that regulate the size of this pool in the adult are poorly defined. Glial cell line‐derived neurotrophic factor (GDNF) is required for establishing this pool in the prepubertal animal, but its in vivo function in the normal adult testis has never been examined directly. We used a chemical‐genetic approach to address this issue. We generated mice carrying a single amino acid mutation (V805A) in Ret, the kinase subunit of the GDNF receptor. This mutation does not affect normal GDNF signaling but renders it susceptible to inhibition by the ATP competitive inhibitor, NA‐PP1. When GDNF signaling was blocked in adults for 11 days, only a few cells remained that expressed the stem spermatogonial markers, Gfrα1 and Zbtb16, and testicular Ret mRNA content was reduced markedly. These decreases were associated with depletion of functional stem spermatogonia; some were lost when GDNF signaling was inhibited for only 2 days while others survived for up to 11 days. However, when signaling was restored, the remaining stem cells proliferated, initiating tissue restoration. In conclusion, these results provide the first direct proof that GDNF acutely regulates the number of spermatogonial stem cells in the normal adult testis. Additionally, these results demonstrate different sensitivities among subpopulation of these stem cells to inhibition of GDNF signaling. STEM CELLS 2012; 30:732–740
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1028