Elucidating a role for Pw1/Peg3 in placenta vascular formation

Abstract

Pw1/Peg3 is a parentally imprinted gene unique to placental mammals, suggesting a specific role in the placenta. Although Pw1/Peg3 is highly expressed in the placenta, the effects of a loss of function during placental development have not been well characterized. To determine Pw1/Peg3 function during placental vascular formation as well as placental remodeling and how this impacts fetal intra-uterine growth in response to hypoxia. A comprehensive study was performed in order to analyze the placental phenotype: at the macroscopic (weight), histological (layers size and composition) and cellular (isolation of specific cell populations) levels. The functional impact of the vascular alteration of the Pw1KO placenta was accessed by the study of placental ability to remodel under hypoxia conditions. We observe that the Pw1/Peg3 is highly expressed in the placental labyrinth zone, i.e. fetal capillaries and syncytiotrophoblast cells, which is the site for fetal-maternal exchange. The mutant placenta displayed an overall lower weight and size coupled with an increase in endothelial and stromal cells and a decrease in pericytes, leading to an altered vascular structure. In order to determine if this altered vascular in the mutant placenta also had a functional impact, we placed pregnant dames in 10% O2 (hypoxic) environment during late fetal development. We observed that Pw1/Peg3 mutants exhibit significantly smaller placentas and embryos with asymmetric intrauterine growth restrictions as compared to wildtypes. These results demonstrate that Pw1/Peg3 is required to regulate placental plasticity in response to environmental challenges, which are critical for fetal and neonatal health, through the establishment of a functional labyrinth vascular network. The loss of Pw1/Peg3 function impairs the development of the vascular network in the labyrinth layer and governs placental remodeling in response to hypoxia.