Hand2 Is an Essential Regulator for Two Notch-Dependent Functions within the Embryonic Endocardium
Nathan J. VanDusen,
Jose Casanovas,
Joshua W. Vincentz,
Beth A. Firulli,
Marco Osterwalder,
Javier Lopez-Rios,
Rolf Zeller,
Bin Zhou,
Joaquim Grego-Bessa,
José Luis De La Pompa,
Weinian Shou,
Anthony B. Firulli
Affiliations
Nathan J. VanDusen
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
Jose Casanovas
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
Joshua W. Vincentz
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
Beth A. Firulli
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
Marco Osterwalder
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
Javier Lopez-Rios
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
Rolf Zeller
Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland
Bin Zhou
Department of Genetics, Albert Einstein College of Medicine, New York, NY 10461, USA
Joaquim Grego-Bessa
Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
José Luis De La Pompa
Cardiovascular Developmental Biology Program, Cardiovascular Development and Repair Department, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain
Weinian Shou
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
Anthony B. Firulli
Riley Heart Research Center, Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA
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.
