title: Hand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium.
abstract: The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1. Additionally, Hand2 participates in endocardium-to-endocardium-based cell signaling, with Hand2 mutant hearts displaying an increased density of coronary lumens. Molecular analyses further reveal dysregulation of several crucial components of Vegf signaling, including VegfA, VegfR2, Nrp1, and VegfR3. Thus, Hand2 functions as a crucial downstream transcriptional effector of endocardial Notch signaling during both cardiogenesis and coronary vasculogenesis.
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: VanDusen
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Casanovas
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Vincentz
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Firulli
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Osterwalder
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Javier
authors.initials: J
authors.lastname: Lopez-Rios
authors.affiliation: Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Zeller
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Grego-Bessa
authors.affiliation: Cardiovascular Developmental Biology Program, Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: De La Pompa
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA.
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.affiliation: Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA. Electronic address: tfirulli@iu.edu.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004699:Endocardium / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism; D039942:Neuropilin-1 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020890:Neuregulin-1; D039942:Neuropilin-1; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3; C498766:Hand2 protein, mouse; C467480:vascular endothelial growth factor A, mouse; C581309:FLT4 protein, human; C000592875:Kdr protein, mouse