Signalling-modulated gene regulatory networks in early mammalian development

Abstract

Early mammalian embryo is a paradigm of dynamic, self-organised process. It involves gene expression, cell division and intercellular signalling. How these processes interact to ensure reproducible development is being often investigated by modelling, which allows to dissect the mechanisms controlling cell fate decisions. In this work, we present two models based on ordinary differential equations describing the first and second specification processes in the mouse embryo. Together, they describe the cell fate decisions leading to the first three cell lineages which form the blastocyst 4.5 days after fertilisation: the trophectoderm, the epiblast and the primitive endoderm. Both specifications rely on multistability, and signalling allows the selection of the appropriate steady-state. In addition to the gene regulatory network, the first specification process is indeed controlled by the Hippo pathway, which is itself controlled by cell polarity and cell-to-cell contacts. This leads to a spatially organised arrangement of cells. The second specification process is controlled by Fgf signalling and leads to a salt and pepper distribution of the two cell types. We discuss the respective mechanisms and their physiological implications.

Keywords: Bistability; Embryonic development; Epiblast; Fgf/Erk signalling; Hippo signalling; Inner cell mass; Primitive endoderm; Tristability; Trophectoderm.