Loss of Hand2 in a population of Periostin lineage cells results in pronounced bradycardia and neonatal death

Nathan J. VanDusen, Joshua W. Vincentz, Beth A. Firulli, Marthe J. Howard, Michael Rubart, Anthony B. Firulli

Research output: Contribution to journalArticle

12 Scopus citations

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 (H2. CKO). We find that Postn-Cre H2. CKOs 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 H2. CKO 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.

Original languageEnglish (US)
Pages (from-to)149-158
Number of pages10
JournalDevelopmental Biology
Volume388
Issue number2
DOIs
StatePublished - Apr 15 2014

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Keywords

  • Basic Helix-loop-Helix (bHLH) transcription factor
  • Bradycardia
  • Hand2
  • Heart development
  • Heart failure
  • Sympathetic neurogenesis

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology
  • Molecular Biology

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