FGF is an essential regulator of the fifth cell division in preimplantation mouse embryos

Fibroblast growth factor (FGF) signaling is required prior to gastrulation in the mouse embryo. To test for the spatial and temporal requirements of FGF signaling, a dominant negative FGF receptor (dnFGFR) was used to make transgenic mouse embryos. In mosaic embryos, cell division ceased at the fifth cell division in all cells that expressed the mutant receptor, but cell death did not increase. After the fifth cell division, the progeny of unaltered cells and cells expressing lacZ continued to accumulate at the same rate, suggesting that the FGF requirement is cell autonomous. In mosaic embryos, lacZ, but not dnFGFR expression was detected in mitotic trophoblasts adjacent to the ICM. Conversely, dnFGFR-expressing extraembryonic ectoderm cells were detected at the abembryonic pole in postmitotic cells. In blastocysts expressing the dnFGFR in all cells, the morphology appeared normal and inner cell masses (ICMs) formed, but resultant embryos had only one-third the number of cells as control embryos. In these blastocysts, cell division had also ceased at the fifth cell division, but cavitation, a concurrent morphogenetic event, initiated and progressed normally. To test for the continuing requirement of FGF, FGFR-3 was overexpressed in all cells and resulted in an increase in cell numbers after the fifth cell cycle. In a model for postimplantation development, addition of FGF-4 to blastocyst outgrowths increased the number of extraembryonic ectoderm cells, suggesting a continuing role for FGF. Thus, FGF signaling induces the cell division of embryonic and extraembryonic cells in the preimplantation mouse embryo starting at the fifth cell division. The signal requirement for FGF is cell autonomous, but is not required to prevent cell death. This provides the first evidence for the necessity of a growth factor before implantation.