title: Cited2 is required in trophoblasts for correct placental capillary patterning.
abstract: CITED2 is a transcriptional co-factor with important roles in many organs of the developing mammalian embryo. Complete deletion of this gene causes severe malformation of the placenta, and results in significantly reduced embryonic growth and death from E14.5. The placenta is a complex organ originating from cells derived from three lineages: the maternal decidua, the trophectoderm, and the extra-embryonic mesoderm. Cited2 is expressed in many of these cell types, but its exact role in the formation of the placenta is unknown. Here we use a conditional deletion approach to remove Cited2 from overlapping subsets of trophectoderm and extra-embryonic mesoderm. We find that Cited2 in sinusoidal trophoblast giant cells and syncytiotrophoblasts is likely to have a non-cell autonomous role in patterning of the pericytes associated with the embryonic capillaries. This function is likely to be mediated by PDGF signaling. Furthermore, we also identify that loss of Cited2 in syncytiotrophoblasts results in the subcellular mislocalization of one of the major lactate transporters in the placenta, SLC16A3 (MCT4). We hypothesize that the embryonic growth retardation observed in Cited2 null embryos is due in part to a disorganized embryonic capillary network, and in part due to abnormalities of the nutrient transport functions of the feto-maternal interface.
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia. Electronic address: j.moreau@victorchang.edu.au.
authors.forename: Julie L M
authors.initials: JL
authors.lastname: Moreau
authors.affiliation: St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address: sartap@bidmc.harvard.edu.
authors.forename: Stanley T
authors.initials: ST
authors.lastname: Artap
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia. Electronic address: h.shi@victorchang.edu.au.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Shi
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address: g.chapman@victorchang.edu.au.
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.affiliation: Human Cancer Genetics Program, The Ohio State University, Colombus, USA. Electronic address: gustavo.leone@osumc.edu.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Leone
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia. Electronic address: d.sparrow@victorchang.edu.au.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, Sydney, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia; School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, Australia. Electronic address: s.dunwoodie@victorchang.edu.au.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000818:Animals; D019521:Body Patterning; D002196:Capillaries / Q000196:embryology*; D002352:Carrier Proteins / Q000378:metabolism; D047108:Embryonic Development; D005260:Female; D017353:Gene Deletion; D051379:Mice; D008810:Mice, Inbred C57BL; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis; D009124:Muscle Proteins / Q000096:biosynthesis; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D020286:Pericytes / Q000166:cytology / Q000502:physiology; D010920:Placenta / Q000098:blood supply* / Q000196:embryology*; D021041:Placental Circulation / Q000235:genetics*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis; D012097:Repressor Proteins / Q000235:genetics*; D027981:Symporters / Q000096:biosynthesis; D015534:Trans-Activators / Q000235:genetics*; D014327:Trophoblasts / Q000201:enzymology*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000199:Actins; D002352:Carrier Proteins; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta; D012097:Repressor Proteins; D027981:Symporters; D015534:Trans-Activators; D000099233:Monocarboxylate Transport Protein 1; C558396:Acta2 protein, mouse; C110087:Cited2 protein, mouse; C491392:Slc16a3 protein, mouse; C498648:Slc16a4 protein, mouse; C075278:platelet-derived growth factor A
keywords: Cited2; Mouse; PDGF signaling; Placenta; Trophoblast; Vasculature