Cyclical expression of GDNF is required for spermatogonial stem cell homeostasis.

Document Type

Article

Publication Date

3-1-2018

Keywords

Animals, Cell Differentiation, Cell Proliferation, Gene Expression Regulation, Glial Cell Line-Derived Neurotrophic Factor, Homeostasis, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Spermatogenesis, Spermatogonia, Stem Cells, Testis

JAX Source

Development 2018 Mar 1; 145(5):dev151555

Volume

145

Issue

5

ISSN

1477-9129

PMID

29440301

DOI

https://doi.org/10.1242/dev.151555

Grant

HD042454UW, CA034196

Abstract

In the murine testis, self-renewal of spermatogonial stem cells (SSCs) requires glial cell line-derived neurotrophic factor (GDNF) secreted from neighboring somatic cells. However, it not clear how GDNF promotes self-renewal in vivo or what downstream signaling pathways are required for SSC maintenance. We found that GDNF is normally expressed cyclically during spermatogenesis. Stage-specific ectopic expression of GDNF caused the accumulation of a GFRA1+ LIN28- Asingle population, which has enhanced SSC activity compared with wild type, suggesting that GDNF normally limits self-renewal to specific stages. Despite the increase in SSC cell number, EdU labeling during steady-stage spermatogenesis, and during recovery after busulfan-mediated spermatogonial depletion, indicated that GDNF promotes self-renewal by blocking differentiation and not by promoting proliferation. Increased GDNF signaling led to increased phosphorylation of AKT3 in undifferentiated spermatogonia, but not of AKT1 or AKT2, and was independent of RPS6 phosphorylation, suggesting that AKT3 functions in SSC self-renewal or progenitor cell expansion. Development 2018 Mar 1; 145(5):dev151555.

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