The AKT1-FOXO4 axis reciprocally regulates hemochorial placentation

Development. 2023 Jan 15;150(2):dev201095. doi: 10.1242/dev.201095. Epub 2023 Jan 17.

Abstract

Hemochorial placentation involves the differentiation of invasive trophoblast cells, specialized cells that possess the capacity to exit the placenta and invade into the uterus where they restructure the vasculature. Invasive trophoblast cells arise from a well-defined compartment within the placenta, referred to as the junctional zone in rat and the extravillous trophoblast cell column in human. In this study, we investigated roles for AKT1, a serine/threonine kinase, in placental development using a genome-edited/loss-of-function rat model. Disruption of AKT1 resulted in placental, fetal and postnatal growth restriction. Forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate, was abundantly expressed in the junctional zone and in invasive trophoblast cells of the rat placentation site. 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, but in opposite directions. In summary, we have identified AKT1 and FOXO4 as part of a regulatory network that reciprocally controls critical indices of hemochorial placenta development.

Keywords: AKT1; FOXO4; Genome editing; Placenta; Pregnancy; Rat; Trophoblast.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Placenta* / metabolism
  • Placentation* / genetics
  • Pregnancy
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Trophoblasts
  • Uterus

Substances

  • Akt1 protein, rat
  • Cell Cycle Proteins
  • Forkhead Transcription Factors
  • FOXO4 protein, rat
  • Proto-Oncogene Proteins c-akt