title: Gene-environment interaction demonstrates the vulnerability of the embryonic heart.
abstract: Mammalian embryos develop in a low oxygen environment. The transcription factor hypoxia inducible factor 1a (HIF1α) is a key element in the cellular response to hypoxia. Complete deletion of Hif1α from the mouse conceptus causes extensive placental, vascular and heart defects, resulting in embryonic lethality. However the precise role of Hif1α in each of these organ systems remains unknown. To further investigate, we conditionally-deleted Hif1α from mesoderm, vasculature and heart individually. Surprisingly, deletion from these tissues did not recapitulate the same severe heart phenotype or embryonic lethality. Placental insufficiency, such as occurs in the complete Hif1α null, results in elevated cellular hypoxia in mouse embryos. We hypothesized that subjecting the Hif1α conditional null embryos to increased hypoxic stress might exacerbate the effects of tissue-specific Hif1α deletion. We tested this hypothesis using a model system mimicking placental insufficiency. We found that the majority of embryos lacking Hif1α in the heart died when exposed to non-physiological hypoxia. This was a heart-specific phenomenon, as HIF1α protein accumulated predominantly in the myocardium of hypoxia-stressed embryos. Our study demonstrates the vulnerability of the heart to lowered oxygen levels, and that under such conditions of non-physiological hypoxia the embryo absolutely requires Hif1α to continue normal development. Importantly, these findings extend our understanding of the roles of Hif1α in cardiovascular development.
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: v.oreilly@victorchang.edu.au.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: O'Reilly
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: kylie.lopesfloro@uqconnect.edu.au.
authors.forename: Kylie
authors.initials: K
authors.lastname: Lopes Floro
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: h.shi@victorchang.edu.au.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Shi
authors.affiliation: School of Molecular Bioscience, Molecular Bioscience Building G08, University of Sydney, NSW 2006, Australia. Electronic address: bogdan.chapman@sydney.edu.au.
authors.forename: Bogdan E
authors.initials: BE
authors.lastname: Chapman
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: jost.preis@gmail.com.
authors.forename: Jost I
authors.initials: JI
authors.lastname: Preis
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia. Electronic address: a.james@victorchang.edu.au.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: James
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia; School of Molecular Bioscience, Molecular Bioscience Building G08, University of Sydney, NSW 2006, Australia. Electronic address: g.chapman@victorchang.edu.au.
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, de Lacy Building, St. Vincent׳s Hospital, Darlinghurst, Sydney, NSW 2010, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: r.harvey@victorchang.edu.au.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Harvey
authors.affiliation: Department of Physiology, Development & Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3 EG, United Kingdom. Electronic address: rsj33@cam.ac.uk.
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.affiliation: School of Molecular Bioscience, Molecular Bioscience Building G08, University of Sydney, NSW 2006, Australia; Department of Radiology, Royal Prince Alfred Hospital, Missenden Road, Camperdown, Sydney, NSW 2050, Australia; Sydney Translational Imaging Laboratory, Sydney Medical School, Edward Ford Building A27, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: sgrieve@med.usyd.edu.au.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Grieve
authors.affiliation: Developmental and Stem Cell Biology Division, Victor Chang Cardiac Research Institute, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, de Lacy Building, St. Vincent׳s Hospital, Darlinghurst, Sydney, NSW 2010, 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, 405 Liverpool Street, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent׳s Clinical School, Faculty of Medicine, University of New South Wales, de Lacy Building, St. Vincent׳s Hospital, Darlinghurst, Sydney, NSW 2010, Australia; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: s.dunwoodie@victorchang.edu.au.
authors.forename: Sally L
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000483:Alleles; D000818:Animals; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D059647:Gene-Environment Interaction; D005838:Genotype; D006321:Heart / Q000196:embryology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D009206:Myocardium / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen
keywords: Gene–environment interaction; HIF1a; Heart development; Hypoxia; Mouse