title: Activation of FGFR(IIIc) isoforms promotes activin-induced mesendoderm development in mouse embryonic stem cells and reduces Sox17 coexpression in EpCAM+ cells.
abstract: Activin induces the formation of definitive endoderm from mouse ES cells dependent on active fibroblast growth factor (Fgf) signaling. Here we report that Fgf4 is dispensable for activin A-induced differentiation of mouse ES cells into endoderm. We find that Fgf4(-/-) cells readily differentiate into definitive endoderm without exogenous administration of Fgf4. Additionally, we investigate the spatio-temporal dynamics of Fgf receptor (FGFR) isoform distribution in activin A-treated ES cell cultures and find that FGFR(III)c isoforms are expressed in DE as well as non-DE populations, whereas FGFR2(III)b and FGFR4 are found specifically enriched in the DE fraction. Ligands that preferentially activate the FGFR(III)c isoforms induce mesendoderm markers T and Gsc, but reduce expression of the DE marker Sox17 in activin-induced EpCAM(+) cells. In contrast, ligands specifically activating FGFR(III)b isoforms have no effect on either population. Activation of FGFR(III)c isoforms results in a strong mitogenic effect on activin A-induced ES cell progeny early in the differentiation period whereas activation of FGFR(III)b isoforms has only a moderate mitogenic effect confined to the late differentiation period. We conclude that FGFR(III)c-isoform activation selectively drives the differentiation of mES cells toward mesendoderm and that Fgf4 is dispensable for the differentiation into definitive endoderm.
authors.affiliation: Department of Stem Cell Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark.
authors.forename: Janny M L
authors.initials: JM
authors.lastname: Peterslund
authors.forename: Palle
authors.initials: P
authors.lastname: Serup
mesh_terms: D028341:Activins / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D004707:Endoderm / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D055760:SOXF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C496446:Fgf4 protein, mouse; D051519:Fibroblast Growth Factor 4; D024002:HMGB Proteins; D020033:Protein Isoforms; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse; C422405:activin A; D028341:Activins; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3