Maternal and fetal genomes interplay through phosphoinositol 3-kinase(PI3K)-p110α signaling to modify placental resource allocation

Abstract

Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.resource allocation | fetus | placenta | PI3K | nutrient transport

C-terminal truncation of Pik3r1 in mice models human lipodystrophic insulin resistance uncoupled from dyslipidemia

“…At E11.5 homozygous embryos were smaller, with poorly developed limb buds and reduced eye pigmentation ( Figure 1A ), while heterozygous embryos were smaller from E15.5 onwards ( Supplemental Figure S2 ). No difference in mass of wild type and heterozygous placentas examined from wild type dams was seen, however vascularisation of the placental exchange region was severely compromised, with around a 40% reduction in vessel density, volume and length at E15.5 (Supplemental Figure S3), as reported previously for placentas heterozygous for a kinase dead p110α catalytic subunit (28). In contrast to that model, however, the size of the placental exchange region (both volume and surface area) and the thickness of the diffusion barrier were normal ( Supplemental Figure S3 ).…”

Competition for Materno-Fetal Resource Partitioning in a Rabbit Model of Undernourished Pregnancy

“…Experiments based on genetic and dietary manipulations have demonstrated that the placenta interprets fetal and maternal interests, adapting its phenotype and function according to resource availability [72–74]. An example of these fascinating adaptations is that undernourished placentas can overcome MFR and maintain or even increase their nutrient transfer capacity to help maintain fetal growth [50].…”

Evaluation of circulating miRNAs during late pregnancy in the mare

“…PI3K/AKT signaling has been shown to play a role in trophectoderm migration [40] and placental resource allocation [41], as well as being implicated in embryonic neurogenesis and angiogenesis [40, 42]. Many of these pathways also work in conjunction with one another; the PI3K and prolactin signaling pathways have been shown to increase pancreatic islet mass and sensitivity to glucose during pregnancy [43]; likely influencing insulin receptor signaling, another affected pathway, simultaneously.…”