AKT1-FOXO4 Axis Regulates Hemochorial Placentation

Abstract: AKT1 is a serine/threonine kinase implicated in fetal, placental, and postnatal growth. In this study, we investigated roles for AKT1 in placental development using a genome-edited/loss-of-function rat model. Both heterozygous and homozygous Akt1 mutant rats were viable and fertile. Disruption of AKT1 resulted in placental, fetal, and postnatal growth restriction. Akt1 null placentas showed deficits in both junctional zone and labyrinth zone size. Robust differences in the transcriptome of wild type versus Akt1 null junctional zones were identified. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone. FOXO4 expression was prominent in the junctional zone and invasive trophoblast cells of the rat placentation site and enhanced following rat trophoblast stem cell differentiation. Foxo4 gene disruption using genome-editing resulted in placentomegaly, including an enlarged junctional zone. AKT1 and FOXO4 regulate the expression of many of the same transcripts expressed by trophoblast cells; however, in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network controlling hemochorial placenta development