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23 December 2016 Dose-dependent functions of fibroblast growth factor 9 regulate the fate of murine xy primordial germ cells
Ferhat Ulu, Sung-Min Kim, Toshifumi Yokoyama, Yukiko Yamazaki
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Male differentiation of primordial germ cells (PGCs) is initiated by the inhibition of entry into meiosis and exposure to male-inducing factor(s), which are regulated by somatic elements of the developing gonad. Fibroblast growth factor 9 (FGF9) produced by pre-Sertoli cells is essential for male gonadal differentiation and also contributes to survival and male differentiation of XY PGCs. However, it is not clear how FGF9 regulates PGC fate. Using a PGC culture system, we identified dose-dependent, fate-determining functions of FGF9 in XY PGCs. Treatment with low levels of FGF9 (0.2 ng/ml) increased expression of male-specific Dnmt3L and Nanos2 in XY PGCs. Conversely, treatment with high levels of FGF9 (25 ng/ml) suppressed male-specific gene expression and stimulated proliferation of XY PGCs. Western blotting showed that low FGF9 treatment enhanced p38 MAPK (mitogen-activated protein kinase) phosphorylation in the same cells. In contrast, high FGF9 treatment significantly stimulated the ERK (extracellular signal-regulated kinase)1/2 signaling pathway in XY PGCs. We investigated the relationship between the ERK1/2 signaling pathway stimulated by high FGF9 and regulation of PGC proliferation. An ERK1/2 inhibitor (U0126) suppressed the PGC proliferation that would otherwise be stimulated by high FGF9 treatment, and increased Nanos2 expression in XY PGCs. Conversely, a p38 MAPK inhibitor (SB202190) significantly suppressed Nanos2 expression that would otherwise be stimulated by low FGF9 in XY PGCs. Taken together, our results suggest that stage-specific expression of FGF9 in XY gonads regulates the balance between proliferation and differentiation of XY PGCs in a dose-dependent manner.

Summary Sentence

FGF9 directly regulates different fates of XY PGCs in a dose-dependent manner: low FGF9 treatment promotes p38 signaling pathway to induce PGC male differentiation, whereas high FGF9 treatment enhances ERK1/2 signaling pathway to proliferate PGCs.

© The Author 2016. Published by Oxford University Press on behalf of Society for the Study of Reproduction. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Ferhat Ulu, Sung-Min Kim, Toshifumi Yokoyama, and Yukiko Yamazaki "Dose-dependent functions of fibroblast growth factor 9 regulate the fate of murine xy primordial germ cells," Biology of Reproduction 96(1), 122-133, (23 December 2016).
Received: 3 August 2016; Accepted: 30 November 2016; Published: 23 December 2016

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