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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.<\/jats:p>","DOI":"10.1242\/dev.201095","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T11:21:01Z","timestamp":1673004061000},"source":"Crossref","is-referenced-by-count":10,"title":["The AKT1-FOXO4 axis reciprocally regulates hemochorial placentation"],"prefix":"10.1242","volume":"150","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2645-7431","authenticated-orcid":false,"given":"Keisuke","family":"Kozai","sequence":"first","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6810-6475","authenticated-orcid":false,"given":"Ayelen","family":"Moreno-Irusta","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khursheed","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mae-Lan","family":"Winchester","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 2 Department of Obstetrics and Gynecology , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6294-5294","authenticated-orcid":false,"given":"Regan L.","family":"Scott","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5301-2724","authenticated-orcid":false,"given":"Mikaela E.","family":"Simon","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanaga","family":"Muto","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc R.","family":"Parrish","sequence":"additional","affiliation":[{"name":"University of Kansas Medical Center 2 Department of Obstetrics and Gynecology , , Kansas City, KS 66160 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7158-1592","authenticated-orcid":false,"given":"Michael J.","family":"Soares","sequence":"additional","affiliation":[{"name":"Institute for Reproductive and Developmental Sciences 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 1 , Department of Pathology & Laboratory Medicine , , Kansas City, KS 66160 , USA"},{"name":"University of Kansas Medical Center 2 Department of Obstetrics and Gynecology , , Kansas City, KS 66160 , USA"},{"name":"Center for Perinatal Research, Children's Mercy Research Institute, Children's Mercy 3 , Kansas City, MO 64108 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,1,17]]},"reference":[{"key":"2023011714052993300_DEV201095C1","first-page":"295","article-title":"Phenotypic analysis of the rat placenta","volume":"121","author":"Ain","year":"2006","journal-title":"Methods Mol. 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