Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal

Seiji Takashima, Mito Kanatsu-Shinohara, Takashi Tanaka, Hiroko Morimoto, Kimiko Inoue, Narumi Ogonuki, Mayumi Jijiwa, Masahide Takahashi, Atsuo Ogura, Takashi Shinohara

Research output: Contribution to journalArticlepeer-review

135 Citations (Scopus)


Spermatogonial stem cells (SSCs) are required for spermatogenesis. Earlier studies showed that glial cell line-derived neurotrophic factor (GDNF) was indispensable for SSC self-renewal by binding to the GFRA1/RET receptor. Mice with mutations in these molecules showed impaired spermatogenesis, which was attributed to SSC depletion. Here we show that SSCs undergo GDNF-independent self-renewal. A small number of spermatogonia formed colonies when testis fragments from a Ret mutant mouse strain were transplanted into heterologous recipients. Moreover, fibroblast growth factor 2 (FGF2) supplementation enabled in vitro SSC expansion without GDNF. Although GDNF-mediated self-renewal signaling required both AKT and MAP2K1/2, the latter was dispensable in FGF2-mediated self-renewal. FGF2-depleted testes exhibited increased levels of GDNF and were enriched for SSCs, suggesting that the balance between FGF2 and GDNF levels influences SSC self-renewal in vivo. Our results show that SSCs exhibit at least two modes of self-renewal and suggest complexity of SSC regulation in vivo.

Original languageEnglish
Pages (from-to)489-502
Number of pages14
JournalStem Cell Reports
Issue number3
Publication statusPublished - 10-03-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology


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