AKT1-FOXO4 Axis Regulates Hemochorial Placentation [Foxo4-KD-rTSC]

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 and their ability to adapt to a physiological stressor. Robust differences in the transcriptome of wild type versus Akt1 null junctional zones were identified. Among the differentially expressed junctional zone transcripts was forkhead box O4 (Foxo4), which encodes a transcription factor and known AKT substrate. FOXO4 expression was prominent in the junctional zone and invasive trophoblast cells of the rat placentation site and enhanced following rat TS 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.AKT1是一种丝氨酸/苏氨酸激酶，参与胎儿、胎盘及产后生长调控。本研究采用基因组编辑/功能丧失型大鼠模型，探究了AKT1在胎盘发育中的作用。结果显示，杂合子与纯合子Akt1突变大鼠均具备存活能力且可正常繁育。AKT1功能缺失会引发胎盘、胎儿及产后生长受限。Akt1纯合缺失的胎盘，其交界区与迷路区的体积均存在缺陷，且无法适应生理应激刺激。研究鉴定出野生型与Akt1纯合缺失胎盘交界区的转录组存在显著差异。在差异表达的交界区转录本中，包含叉头框蛋白O4（forkhead box O4, Foxo4）——该基因编码一种转录因子，同时也是已知的AKT底物。FOXO4在大鼠胎盘着床部位的交界区及侵袭性滋养层细胞中高表达，并在大鼠TS细胞分化过程中表达上调。通过基因组编辑敲除Foxo4基因可导致胎盘肥大，表现为交界区体积增大。AKT1与FOXO4可调控滋养层细胞表达的大量共有转录本，但二者的调控方向相反。综上，本研究确认AKT1与FOXO4共同构成调控血绒毛膜胎盘发育的信号网络。