title: Fgf9 inhibition of meiotic differentiation in spermatogonia is mediated by Erk-dependent activation of Nodal-Smad2/3 signaling and is antagonized by Kit Ligand.
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.
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tassinari
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Campolo
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cesarini
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Todaro
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Dolci
authors.affiliation: Dipartimento di Biomedicina e Prevenzione, Università degli Studi di Roma Tor Vergata, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Rossi
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D051525:Fibroblast Growth Factor 9 / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D055457:Nodal Protein / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction; D051899:Smad2 Protein / Q000096:biosynthesis*; D013093:Spermatogonia / Q000254:growth & development / Q000378:metabolism; D019089:Stem Cell Factor / Q000096:biosynthesis*
chemical_list: C496459:FGF9 protein, human; D051525:Fibroblast Growth Factor 9; C526007:NODAL protein, human; D055457:Nodal Protein; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D019089:Stem Cell Factor; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019869:Phosphatidylinositol 3-Kinases