Akt1-Foxo4 Axis Reciproaclly 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

Single-cell assessment of trophoblast stem cell-based organoids as human placenta-modeling platforms

“…Interestingly, FOXO4 has been implicated in redox signalling 44, 45 , tumour suppression 46 , stem cell maintenance 47 , and the inhibition of proliferation through E2F4 48 , another CTB-specific TF identified here. Additionally, FOXO4 regulates rat placenta development 49 and inhibits epithelial-mesenchymal transition 50 , a process involved in extravillous trophoblast maturation. The regulation of FOXO4 by hypoxia-related processes (i.e., redox signaling, E2F4 induction) suggests in utero hypoxia may induce FOXO4 to regulate CTB proliferation, renewal, and maintenance, although these interactions will need to be tested.…”