title: Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion.
abstract: OBJECTIVE
  The strategies that control formation of the ventricular wall during heart development are not well understood. In previous studies, we documented IGF2 as a major mitogenic signal that controls ventricular cardiomyocyte proliferation and chamber wall expansion. Our objective in this study was to define the tissue source of IGF2 in heart development and the upstream pathways that control its expression.
  
  
  RESULTS
  Using a number of mouse genetic tools, we confirm that the critical source of IGF2 is the epicardium. We find that epicardial Igf2 expression is controlled in a biphasic manner, first induced by erythropoietin and then regulated by oxygen and glucose with onset of placental function. Both processes are independently controlled by retinoic acid signalling.
  
  
  CONCLUSIONS
  Our results demonstrate that ventricular wall cardiomyocyte proliferation is subdivided into distinct regulatory phases. Each involves instructive cues that originate outside the heart and thereby act on the epicardium in an endocrine manner, a mode of regulation that is mostly unknown in embryogenesis.
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, 1425 San Pablo Street, BCC-511, Los Angeles, CA 90033, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, 1425 San Pablo Street, BCC-511, Los Angeles, CA 90033, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Cavallero
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, 1425 San Pablo Street, BCC-511, Los Angeles, CA 90033, USA.
authors.forename: Kristine D
authors.initials: KD
authors.lastname: Estrada
authors.affiliation: MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology and NIHR Cambridge Biomedical Research Centre, University of Cambridge Metabolic Research Laboratories, Cambridge, UK Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
authors.forename: Ionel
authors.initials: I
authors.lastname: Sandovici
authors.affiliation: Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: S Ram
authors.initials: SR
authors.lastname: Kumar
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Makita
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Ching-Ling
authors.initials: CL
authors.lastname: Lien
authors.affiliation: MRC Metabolic Diseases Unit, Department of Obstetrics and Gynaecology and NIHR Cambridge Biomedical Research Centre, University of Cambridge Metabolic Research Laboratories, Cambridge, UK Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
authors.forename: Miguel
authors.initials: M
authors.lastname: Constancia
authors.affiliation: Broad Center for Regenerative Medicine and Stem Cell Research, University of Southern California, 1425 San Pablo Street, BCC-511, Los Angeles, CA 90033, USA sucov@usc.edu.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Sucov
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D004921:Erythropoietin / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D005947:Glucose / Q000378:metabolism; D006352:Heart Ventricles / Q000196:embryology / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism*; D038081:Organogenesis; D010100:Oxygen / Q000378:metabolism; D010496:Pericardium / Q000196:embryology / Q000378:metabolism*; D010641:Phenotype; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction
chemical_list: C513121:IGF2 protein, mouse; C000607072:Rara protein, mouse; D017467:Receptors, Erythropoietin; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D004921:Erythropoietin; D007335:Insulin-Like Growth Factor II; D005947:Glucose; D010100:Oxygen
keywords: Cardiomyocyte proliferation; Endocrine signalling; Epicardium; Heart development