title: FGF8-FGFR1 signaling acts as a niche factor for maintaining undifferentiated spermatogonia in the mouse.
abstract: In mammalian testes, spermatogonial stem cells (SSCs) maintain spermatogenesis over a long period of time by undergoing self-renewal and differentiation. SSCs are among the most primitive of spermatogenic cells (undifferentiated spermatogonia), and their activities are strictly regulated by extrinsic niche factors. However, the factors that constitute a testicular niche remain poorly understood. In this study, we demonstrate that fibroblast growth factor (FGF) signaling maintains undifferentiated spermatogonia through activating ERK1/2 signaling in vivo. Undifferentiated spermatogonia comprise GFRA1(+) and NANOS3(+) subpopulations, which are likely to undergo self-renewal and enter the differentiation pathway, respectively. In the testis, Fgfr1 was expressed in the entire population of undifferentiated spermatogonia, and deleting FGFR1 in spermatogenic cells partially inactivated ERK1/2 and resulted in reduced numbers of both GFRA1(+) and NANOS3(+) cells. In addition, Fgf8 was expressed in spermatogenic cells, and loss- and gain-of-function models of FGF8 demonstrated that FGF8 positively regulated the numbers of undifferentiated spermatogonia through FGFR1, particularly among NANOS3(+) cells. Finally we show a possible involvement of FGF signaling in the reversion from NANOS3(+) into GFRA1(+) undifferentiated spermatogonia. Taken together, our data suggest that FGF signaling is an important component of the testicular niche and has a unique function for maintaining undifferentiated spermatogonia.
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Mishima, Shizuoka, Japan.
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Hasegawa
authors.affiliation: Division of Mammalian Development, National Institute of Genetics, Mishima, Shizuoka, Japan Department of Genetics, Sokendai, Mishima, Shizuoka, Japan ysaga@nig.ac.jp.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics*; D013737:Testis / Q000166:cytology* / Q000378:metabolism
chemical_list: C496457:Fgf8 protein, mouse; D051524:Fibroblast Growth Factor 8; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Sertoli cells; developmental biology; knockout model; signal transduction; spermatogonial stem cells; transgenic model