title: Forkhead factor FoxO1 is essential for placental morphogenesis in the developing embryo.
abstract: Forkhead box O1 (FoxO1), a member of the Forkhead box-containing O family of transcription factors, is a key regulator of numerous genes that govern a wide array of cellular functions, including differentiation, homeostasis, and survival. However, the role of FoxO1 in development remains elusive. Here, we describe an essential and previously undefined role for FoxO1 in placental development. We demonstrate that FoxO1-null embryos up to embryonic day 9.0 (E9.0) are indistinguishable, including their morphology, cardiovascular structure, and vascular gene expression, from wild-type (WT) littermates. However, FoxO1-nulls manifested a profoundly swollen/hydropic allantois, which failed to fuse with the chorion, a phenotype that leads to subsequent cardiovascular malformation, progressive apoptotic cell death, and embryonic lethality at E10.5. Quantitative RT-PCR analysis of genes involved in placental development revealed significant attenuation of VCAM1 expression in FoxO1-null embryos. Using immunohistochemical, transcriptional, and chromatin immunoprecipitation assays, we further discovered that FoxO1 is an essential upstream regulator of the VCAM1 gene. Collectively, our findings provide critical molecular insight into a unique FoxO1-VCAM1 axis that governs placental morphogenesis, a process that is essential for subsequent normal cardiovascular development and fetal life.
authors.affiliation: Department of Internal Medicine, Cardiology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA. anwarul.ferdous@utsouthwestern.edu
authors.forename: Anwarul
authors.initials: A
authors.lastname: Ferdous
authors.forename: Jesse
authors.initials: J
authors.lastname: Morris
authors.forename: Mohammad Joynal
authors.initials: MJ
authors.lastname: Abedin
authors.forename: Shandon
authors.initials: S
authors.lastname: Collins
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D010929:Placentation; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D019010:Vascular Cell Adhesion Molecule-1