Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway

Abstract

(2015) Binding of FGF2 to FGFR2 in an autocrine mode in trophectoderm cells is indispensable for mouse blastocyst formation through PKC-p38 pathway, Cell Cycle, 14:20, 3318-3330, DOI: 10.1080/15384101.2015 Keywords: blastocyst formation, fibroblast growth factor 2 (FGF2), fibroblast growth factor receptor 2 (FGFR2), protein kinase C (PKC), p38 MAPK Fibroblast growth factors (FGF1, FGF2 and FGF4) and fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) have been reported to be expressed in preimplantation embryos and be required for their development. However, the functions of these molecules in trophectoderm cells (TEs) that lead to the formation of the blastocyst as well as the underlying mechanism have not been elucidated. The present study has demonstrated for the first time that endogenous FGF2 secreted by TEs can regulate protein expression and distribution in TEs via the FGFR2-mediated activation of PKC and p38, which are important for the development of expanded blastocysts. This finding provides the first explanation for the long-observed phenomenon that only high concentrations of exogenous FGFs have effects on embryonic development, but in vivo the amount of endogenous FGFs are trace. Besides, the present results suggest that FGF2/FGFR2 may act in an autocrine fashion and activate the downstream PKC/p38 pathway in TEs during expanded blastocyst formation.

p38 (Mapk14/11) occupies a regulatory node governing entry into primitive endoderm differentiation during preimplantation mouse embryo development

“…Previous studies investigating the role of p38-Mapk14/11 during preimplantation mouse embryo development have used small compound pharmacological inhibition strategies and uncovered a requirement during the morula/blastocyst transition stage, with p38-Mapk14/11 inhibited embryos typically exhibiting arrested development, associated with failures in blastocoel formation and associated TE cell function [ 19 , 30 , 31 ]. Given that both the TE and PrE can be considered as somewhat similar extraembryonic and highly polarized epithelial blastocyst tissues, we hypothesized that p38-Mapk14/11 may also have a role in the differentiation of PrE and hence blastocyst maturation, and, moreover, that this potential role could be assayed using a similar pharmacological inhibition approach, only modified to provide the p38-Mapk14/11 inhibiting drug (SB220025) after the described sensitive morula-to-blastocyst transition.…”

“…As previously discussed, the role of Fgf-ligands in the specification of the PrE cell lineage is well described [ 15 – 18 ]. We therefore wanted to investigate if Fgfr-mediated cell signalling during specification of the PrE was acting, in part, via the activation of p38-Mapk14/11, as has recently been shown during TE specification [ 19 ]. Accordingly, we used a well-characterized and specific chemical inhibitor, SU5402 [ 43 ], that has been widely used in preimplantation mouse embryo studies [ 17 , 22 ] to functionally block Fgfr, and assayed for p38-Mapk14/11-dependent PrE phenotypes.…”

“…However, it may be explained by such cells having already passed a temporal PrE commitment point, governed by p38-Mapk14/11, by the developmental time the inhibitor was provided, a commitment point not passed for the remaining ICM cells. Indeed, to avoid causing arrested development at the morula to blastocyst transition (as observed when we provided the p38-Mapk14/11 inhibitor from the eight-cell/E2.5 stage, see electronic supplementary material, figure S1 and in other reported literature [ 19 , 30 , 31 ]), we were compelled to provide the inhibitor from the E3.5 developmental timepoint at the earliest (i.e. after specification of the TE and formation of the blastocoel).…”

Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions

“…Other Fgf ligands ( Fgf3, Fgf13 ) and receptors ( Fgfr1, Fgfr4 ) are differentially expressed within the ICM (Ohnishi et al, ), but their putative role in lineage segregation has not been explored. Fgf2 and Fgfr2 are also expressed in the TE (Haffner‐Krausz et al, ; Kunath et al, ; Yang et al, ), and they may be implicated in the proper cavitation of the blastocyst (Yang et al, ). Furthermore, the differential expression of Fgf4 and Fgfr2 is implicated in the later specification of TE derivatives, as well as in the establishment and maintenance of TS cells (Tanaka et al, ; Haffner‐Krausz et al, ).…”

Bone Research Society 2015

“…FGF1-10, FGF16-18, FGF-20 and FGF-22 are secreted ligands with paracrine signalling properties and bind to FGFRs in close association with heparan sulphate proteoglycan (HSPG) co-factors. In contrast, FGF19, FGF-21 and FGF-23 are endocrine molecules that require Klotho proteins to activate FGFRs (Yang et al, 2015, Katoh, 2016, Sarabipour and Hristova, 2016) .…”