Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse.

Xiwen Hu,Jingli Zhang,Sun-Wei Guo,Qianqian Zhang,Guang Wang,Quliang Gu,Jiangchao Li,Xuesong Yang,Yuxiang Ye,Xiaohan Zhang,Lingyun Zheng,Lijing Wang

doi:10.1038/srep28201

Abstract

Maternal PI3K p110δ has been implicated in smaller litter sizes in mice, but its underlying mechanism remains unclear. The placenta is an indispensable chimeric organ that supports mammalian embryonic development. Using a mouse model of genetic inactivation of PI3K p110δ (p110δD910A/D910A), we show that fetuses carried by p110δD910A/D910A females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110δD910A/D910A females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110δ was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110δ inactivation affected normal TGCs generation and expansion, impeded the branching of chorioallantoic placenta but enhanced the expression of matrix metalloproteinases (MMP-2, MMP-12). Poor vasculature support for the developing fetoplacental unit resulted in fetal death or gross growth retardation. These data, taken together, provide the first in vivo evidence that p110δ may play an important role in placental vascularization through manipulating trophoblast giant cell.

Highlights

We evaluated the reproductive capacity and examined related histology and morphology in mice p110δD 910A/D910A
Previous reports have demonstrated that homozygous p110δinactive mice (p110δD 910A/D910A) were viable and fertile, without any gross anatomical or behavioral abnormalities, unlike p110α/βmutant mice[30,37,38]
We found that matrix metalloproteinases (MMPs)-12 and MMP2 mainly located in cytoplasm of trophoblast cells, and their expression levels were both elevated in p110δD 910A/D910A group (Fig. 5C,F)

Summary

Introduction

We first demonstrated that p110δis highly expressed in P-TGCs, which can facilitate initial maternal vascular connections, induce uterine decidualization, regulate cell differentiation and maternal physiology, produce angiogenic and hematopoietic hormones, and may be involved in establishing the parietal yolk sac before circulation into the mature placenta. These results demonstrate that p110δis a crucial PI3K component that mediates TGCs function and placentation

Methods

Results

Conclusion