Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus
Previous studies suggest that the placental supply of nutrients to the fetus adapts according to fetal demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier work in mice has revealed that loss of the phosphoinositide 3-kinase p110 impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110 in the epiblast-derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental development and transfer function. Using conditional gene manipulations to knock-down p110 either by [~]50% or [~]100% in the fetal lineages and/or trophoblast, this study shows that p110 in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of fetal p110 caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110 also resulted in abnormal placental development, although fetuses were viable. However, in response to complete loss of trophoblast p110, the placenta failed to transport sufficient amino acid to match fetal demands for growth. Using RNA-seq, we identified several genes downstream of p110 in the trophoblast that are important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 genome targeting showed that loss of p110 differentially affects the expression of genes in trophoblast and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110 signaling in the different compartments of the conceptus, which control fetal resource acquisition and ultimately affect healthy growth.\n\nOne Sentence SummaryFetal and trophoblast p110 modify resource allocation