title: Functional differences between GDNF-dependent and FGF2-dependent mouse spermatogonial stem cell self-renewal.
abstract: 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.
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Seiji
authors: S
authors: Takashima
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; Japan Science and Technology Agency, PRESTO, Kyoto 606-8501, Japan.
authors: Mito
authors: M
authors: Kanatsu-Shinohara
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Takashi
authors: T
authors: Tanaka
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors: Hiroko
authors: H
authors: Morimoto
authors: The Institute for Physical and Chemical Research (RIKEN), Bioresource Center, Tsukuba 305-0074, Japan.
authors: Kimiko
authors: K
authors: Inoue
authors: The Institute for Physical and Chemical Research (RIKEN), Bioresource Center, Tsukuba 305-0074, Japan.
authors: Narumi
authors: N
authors: Ogonuki
authors: Department of Pathology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
authors: Mayumi
authors: M
authors: Jijiwa
authors: Department of Pathology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan.
authors: Masahide
authors: M
authors: Takahashi
authors: The Institute for Physical and Chemical Research (RIKEN), Bioresource Center, Tsukuba 305-0074, Japan.
authors: Atsuo
authors: A
authors: Ogura
authors: Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. Electronic address: tshinoha@virus.kyoto-u.ac.jp.
authors: Takashi
authors: T
authors: Shinohara
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D000066673:Cell Self Renewal; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D015870:Gene Expression; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D012671:Seminiferous Tubules / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013737:Testis / Q000378:metabolism
chemical_list: C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D016222:Fibroblast Growth Factor 2; D051096:Proto-Oncogene Proteins c-ret