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.

Keratinocyte Growth Factor and Dexamethasone Plus Elevated cAMP Levels Synergistically Support Pluripotent Stem Cell Differentiation into Alveolar Epithelial Type II Cells

“…Arguing against an additional very early KGF effect on the formation of (mes)endoderm (first stage, Fig. 6), and confirming recent data of Peterslund and Serup, 55 no increased formation of Bry-GFP pos or Foxa2-huCD4 pos ESC derivatives was observed after early KGF application ( Supplementary Fig. S3C,D).…”

FGFR families: biological functions and therapeutic interventions in tumors

“…In contrast, FGFR2 expression is increased during the differentiation of mesenchymal stromal cells to osteoblasts, while FGFR1 expression in the process of adipocyte differentiation is increased; both processes are accompanied by an increase in FGFRL1 levels 93 . During mouse embryonic development, the FGFRIIIc isoform drives the differentiation of embryonic stem cells into the endoderm 114 …”

“…93 During mouse embryonic development, the FGFRIIIc isoform drives the differentiation of embryonic stem cells into the endoderm. 114 N-cadherin targets the FGFR to inhibit its ubiquitination and lysosomal degradation, leading to ERK1/2 phosphorylation, which is essential for the migration of neocortical projection neurons. 115 FGFR also regulates the proliferation and migration of lymphatic vessel endothelial cells by promoting glycolysis.…”

Dual Lineage‐Specific Expression of Sox17 During Mouse Embryogenesis

“…Epithelial cells of the gut tube endoderm maintain Sox17 expression until approximately E8.5 as they undergo specification into distinct endoderm-derived organs [5][6][7][8]. Expression of Sox17 in endoderm, albeit transient, has led to this gene being widely used as a marker for definitive endoderm in studies using embryonic stem cells (ESCs) [9][10][11][12].…”