Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus

Abstract

32Previous studies suggest that the placental supply of nutrients to the fetus adapts according to fetal 33 demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier 34 work in mice has revealed that loss of the phosphoinositide 3-kinase p110α impairs feto-placental growth 35 but placental nutrient supply is adaptively increased. Here we explore the role of p110α in the epiblast-36 derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental 37 development and transfer function. Using conditional gene manipulations to knock-down p110α either by 38 ~50% or ~100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is 39 essential for prenatal development and a major regulator of placental phenotype in mice. Complete loss of 40 fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and 41 impaired placental formation and nutrient transport. Loss of trophoblast p110α also resulted in abnormal 42 placental development, although fetuses were viable. However, in response to complete loss of 43 trophoblast p110α, the placenta failed to transport sufficient amino acid to match fetal demands for 44 growth. Using RNA-seq, we identified several genes downstream of p110α in the trophoblast that are 45 important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 46 genome targeting showed that loss of p110α differentially affects the expression of genes in trophoblast 47 and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110α signaling in the 48 2 different compartments of the conceptus, which control fetal resource acquisition and ultimately affect 49 healthy growth. 50 51

Placental adaptations supporting fetal growth during normal and adverse gestational environments

“…While fetuses are growth-restricted in early gestation in this PI3K-p110α deficient mouse model, the deficit in fetal growth is less towards term as the morphologically impaired placenta adaptively transports more glucose and amino acid (system A) to the fetus . Cell-specific gene targeting in mice has since revealed that retention of PI3K-p110α signalling ability in the trophoblast lineage of the developing conceptus is critical for mediating the adaptive upregulation of placental system A amino acid transport that is optimizing fetal growth towards term (Lopez-Tello, Khaira, et al, 2019). Other work has indeed highlighted the important role for PI3K signalling in promoting the formation and function of trophoblast lineages (Lee et al, 2019).…”