title: Loss of Hand2 in a population of Periostin lineage cells results in pronounced bradycardia and neonatal death.
abstract: The Periostin Cre (Postn-Cre) lineage includes endocardial and neural crest derived mesenchymal cells of the cardiac cushions, neural crest-derived components of the sympathetic and enteric nervous systems, and cardiac fibroblasts. In this study, we use the Postn-Cre transgenic allele to conditionally ablate Hand2 (H2CKO). We find that Postn-Cre H2CKOs die shortly after birth despite a lack of obvious cardiac structural defects. To ascertain the cause of death, we performed a detailed comparison of the Postn-Cre lineage and Hand2 expression at mid and late stages of embryonic development. Gene expression analyses demonstrate that Postn-Cre ablates Hand2 from the adrenal medulla as well as the sphenopalatine ganglia of the head. In both cases, Hand2 loss-of-function dramatically reduces expression of Dopamine Beta Hydroxylase (Dbh), a gene encoding a crucial catecholaminergic biosynthetic enzyme. Expression of the genes Tyrosine Hydroxylase (Th) and Phenylethanolamine N-methyltransferase (Pnmt), which also encode essential catecholaminergic enzymes, were severely reduced in postnatal adrenal glands. Electrocardiograms demonstrate that 3-day postnatal Postn-Cre H2CKO pups exhibit sinus bradycardia. In conjunction with the aforementioned gene expression analyses, these results strongly suggest that the observed postnatal lethality occurs due to a catecholamine deficiency and subsequent heart failure.
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5225, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: VanDusen
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5225, USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Vincentz
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5225, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Firulli
authors.affiliation: Department of Neurosciences and Program in Neurosciences and Neurological Disorders, University of Toledo Health Sciences Campus, Toledo, OH 43614, USA.
authors.forename: Marthe J
authors.initials: MJ
authors.lastname: Howard
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5225, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart
authors.affiliation: Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Departments of Pediatrics and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 West Walnut Street, Indianapolis, IN 46202-5225, USA. Electronic address: tfirulli@iu.edu.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D001919:Bradycardia / Q000235:genetics*; D019070:Cell Lineage; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C498766:Hand2 protein, mouse
keywords: Basic Helix-loop-Helix (bHLH) transcription factor; Bradycardia; Hand2; Heart development; Heart failure; Sympathetic neurogenesis