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

Maternal PI3K p110 delta 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 p110 delta (p110 delta(D910A/D910A)), we show that fetuses carried by p110 delta(D910A/D910A) females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110 delta(D910A/D910A) females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110 delta was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110 delta 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 p110 delta may play an important role in placental vascularization through manipulating trophoblast giant cell.