Abstract
Both fibroblast growth factor 9 (Fgf9) and Kit Ligand (Kl) signal through tyrosine kinase receptors, yet they exert opposite effects on meiotic differentiation in postnatal spermatogonia, Fgf9 acting as a meiosis-inhibiting substance and Kl acting as a promoter of the differentiation process. To understand the molecular mechanisms that might underlie this difference, we tried to dissect the intracellular signaling elicited by these two growth factors. We found that both Fgf9 and Kl stimulate Erk1/2 activation in Kit+ (differentiating) spermatogonia, even though with different time courses, whereas Kl, but not Fgf9, elicits activation of the Pi3k-Akt pathway. Sustained Erk1/2 activity promoted by Fgf9 is required for induction of the autocrine Cripto-Nodal-Smad2/3 signaling loop in these cells. Nodal signaling, in turn, is essential to mediate Fgf9 suppression of the meiotic program, including inhibition of Stra8 and Scp3 expression and induction of the meiotic gatekeeper Nanos2. On the contrary, sustained activation of the Pi3k-Akt pathway is required for the induction of Stra8 expression elicited by Kl and retinoic acid. Moreover, we found that Kl treatment impairs Nodal mRNA expression and Fgf9-mediated Nanos2 induction, reinforcing the antagonistic effect of these two growth factors on the meiotic fate of male germ cells.
Highlights
Stimulates Kit expression in spermatogonia and Kit Ligand (Kl) expression in Sertoli cells.[1]
We show that Kl and Fgf[9], both stimulating receptor tyrosine kinase activities, act on the same germ cell type (Kit+ spermatogonia), yet they exert opposite effects
We aimed to dissect the differences in the signaling pathways activated by these two antagonistic growth factors and to identify the events that lead to meiotic entry (Kl) or meiotic inhibition (Fgf9) in differentiating spermatogonia
Summary
Stimulates Kit expression in spermatogonia and Kit Ligand (Kl) expression in Sertoli cells.[1] Kl is essential to promote the mitotic expansion of Kit+ premeiotic germ cells.[2] the concerted action of both RA and Kl can induce meiotic entry of in vitro cultured Kit+ spermatogonia.[1] both RA and Kl increase the expression of genes that are fundamental for the beginning of the meiotic process,[1,3] and in particular of Stimulated by Retinoic Acid Gene 8 (Stra8), which is essential for the switch from the mitotic cell cycle to the meiotic program.[1] Selective inhibitors of Kit tyrosine-kinase activity block both RA- and Kl-induced meiotic entry, suggesting that the two factors converge on common, Kit-dependent, signaling pathways.[1] RA- and Kl-induced meiotic entry is mediated, at least in part, by activation of the Pi3k-Akt pathway. Kl promotes meiotic differentiation through the activation of the Pi3k-Akt pathway and inhibition of Nodal expression
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