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. 2018 Oct 1;442(1):155-161.
doi: 10.1016/j.ydbio.2018.07.010. Epub 2018 Jul 17.

Distinct mechanisms for PDGF and FGF signaling in primitive endoderm development

Andrei Molotkov  1 , Philippe Soriano  2
Affiliations

Distinct mechanisms for PDGF and FGF signaling in primitive endoderm development

Andrei Molotkov et al. Dev Biol. .

Abstract

FGF signaling is known to play a critical role in the specification of primitive endoderm (PrE) and epiblast (Epi) from the inner cell mass (ICM) during mouse preimplantation development, but how FGFs synergize with other growth factor signaling pathways is unknown. Because PDGFRα signaling has also been implicated in the PrE, we investigated the coordinate functions of PDGFRα together with FGFR1 or FGFR2 in PrE development. PrE development was abrogated in Pdgfra; Fgfr1 compound mutants, or significantly reduced in Pdgfra; Fgfr2 or PdgfraPI3K; Fgfr2 compound mutants. We provide evidence that both Fgfr2 and Pdgfra play roles in PrE cell survival while Fgfr1 controls PrE cell specification. Our results suggest a model where FGFR1-engaged ERK1/2 signaling governs PrE specification while PDGFRα- and by analogy possibly FGFR2- engaged PI3K signaling regulates PrE survival and positioning in the embryo. Together, these studies indicate how multiple growth factors and signaling pathways can cooperate in preimplantation development.

Keywords: Cell specification; ERK1/2; PI3K; Preimplantation; Survival.

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Figures

Figure 1.
Figure 1.
Expression of Fgfr2 and Pdgfra in E3.0 and E3.5 preimplantation embryos. Note, while Fgfr2mCherry and PdgfraH2B-GFP are differentially expressed in ICM cells at E3.0, both receptors are expressed in the same cells in E3.5 expanded embryos (E3.5 + 48h). Green background fluorescence in E3.0 and E3.5 embryos is due to the presence of the Zona Pellucida that surrounds the embryos. *, blastocoel cavity. Scale bars, 50 μm.
Figure 2.
Figure 2.
PrE development is deficient in Fgfr2−/−; Pdgfra−/− embryos. (A) E3.5 embryos were cultured for 48h in DMEM and stained with antibodies to NANOG (red) and GATA4 (green). DAPI (white) was used to counter-stain nuclei. Number of Epi (B), PrE (C) and total cells (D) were counted in E3.5 embryos cultured for 48h in DMEM. Percentages of Epi (E) and PrE (F) cells relative to the total number of cells are shown. (G) Number of ICM cells is shown. Data represented as mean + SEM. *, p=0.02; **, p=0.006. Scale bars, 50 μm.
Figure 3.
Figure 3.
PrE development is disrupted in Fgfr1−/−; Pdgfra−/− embryos. (A) Embryos were dissected at E3.5, cultured for 48h in DMEM and stained with antibodies to NANOG (green), GATA4 (red) and CDX2 (white). Number of Epi (B), PrE (C) and total number of cells (D) were counted and are shown for the individual embryos. The proportion of Epi (E) and PrE (F) cells in the embryos are shown. (G) Number of ICM cells. Data represented as mean + SEM. *, p=0.002; **, p=0.003. Scale bars, 50 μm.
Figure 4.
Figure 4.
PI3K is the main signaling pathway downstream PDGFRα in PrE development. (A) Two E3.5 Fgfr1−/−; PdgfraPI3K/PI3K embryos are shown. NANOG (green) labels Epi cells, GATA4 (red) labels PrE. DAPI (blue) used to counter label cell nuclei. (B) Number of PrE cells in Fgfr1−/−; PdgfraPI3K/PI3K embryos (red box) are shown compared to Fgfr1 & Pdgfra compound mutants. Scale bars, 50 μm.
Figure 5.
Figure 5.
Model for FGF and PDGF signaling in PrE development. At the mid-blastocyst stage, FGF4 is produced by a subpopulation of the ICM cells and signals in a paracrine fashion through ERK1/2 to induce PrE cells. In expanded blastocysts, PDGFA signaling to PDGFRα, and potentially FGF4 signaling to FGFR2, activates PI3K in newly forming PrE cells, which controls their survival.
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References

    1. Artus J, Kang M, Cohen-Tannoudji M, Hadjantonakis AK, 2013. PDGF Signaling Is Required for Primitive Endoderm Cell Survival in the Inner Cell Mass of the Mouse Blastocyst. Stem cells (Dayton, Ohio) 31, 1932–1941. - PMC - PubMed
    1. Artus J, Panthier JJ, Hadjantonakis AK, 2010. A role for PDGF signaling in expansion of the extra-embryonic endoderm lineage of the mouse blastocyst. Development (Cambridge, England) 137, 3361–3372. - PMC - PubMed
    1. Brewer JR, Mazot P, Soriano P, 2016. Genetic insights into the mechanisms of Fgf signaling. Genes & development 30, 751–771. - PMC - PubMed
    1. Brewer JR, Molotkov A, Mazot P, Hoch RV, Soriano P, 2015. Fgfr1 regulates development through the combinatorial use of signaling proteins. Genes & development 29, 1863–1874. - PMC - PubMed
    1. Chazaud C, Yamanaka Y, Pawson T, Rossant J, 2006. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Developmental cell 10, 615–624. - PubMed

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