Institute for Reproductive and Developmental Sciences, Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Development. 2023 Jan 15;150(2). doi: 10.1242/dev.201095. Epub 2023 Jan 17.
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.
绒毛膜胎盘涉及侵袭性滋养细胞的分化，这些特殊的细胞具有离开胎盘并侵入子宫的能力，在那里它们重塑血管系统。侵袭性滋养细胞起源于胎盘内一个明确的区域，在大鼠中称为连接区，在人类中称为绒毛外滋养细胞柱。在这项研究中，我们使用基因组编辑/功能丧失的大鼠模型研究了丝氨酸/苏氨酸激酶 AKT1 在胎盘发育中的作用。AKT1 的破坏导致胎盘、胎儿和产后生长受限。叉头框 O4（Foxo4）是一种转录因子，也是已知的 AKT 底物，在大鼠胎盘部位的连接区和侵袭性滋养细胞中大量表达。使用基因组编辑破坏 Foxo4 基因导致胎盘肿大，包括连接区增大。AKT1 和 FOXO4 调节许多由滋养细胞表达的相同转录本的表达，但方向相反。总之，我们已经确定 AKT1 和 FOXO4 是一个调节网络的一部分，该网络相互控制绒毛膜胎盘发育的关键指标。
