title: Hand2 elevates cardiomyocyte production during zebrafish heart development and regeneration.
abstract: Embryonic heart formation requires the production of an appropriate number of cardiomyocytes; likewise, cardiac regeneration following injury relies upon the recovery of lost cardiomyocytes. The basic helix-loop-helix (bHLH) transcription factor Hand2 has been implicated in promoting cardiomyocyte formation. It is unclear, however, whether Hand2 plays an instructive or permissive role during this process. Here, we find that overexpression of hand2 in the early zebrafish embryo is able to enhance cardiomyocyte production, resulting in an enlarged heart with a striking increase in the size of the outflow tract. Our evidence indicates that these increases are dependent on the interactions of Hand2 in multimeric complexes and are independent of direct DNA binding by Hand2. Proliferation assays reveal that hand2 can impact cardiomyocyte production by promoting division of late-differentiating cardiac progenitors within the second heart field. Additionally, our data suggest that hand2 can influence cardiomyocyte production by altering the patterning of the anterior lateral plate mesoderm, potentially favoring formation of the first heart field at the expense of hematopoietic and vascular lineages. The potency of hand2 during embryonic cardiogenesis suggested that hand2 could also impact cardiac regeneration in adult zebrafish; indeed, we find that overexpression of hand2 can augment the regenerative proliferation of cardiomyocytes in response to injury. Together, our studies demonstrate that hand2 can drive cardiomyocyte production in multiple contexts and through multiple mechanisms. These results contribute to our understanding of the potential origins of congenital heart disease and inform future strategies in regenerative medicine.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA Developmental Genetics Program and Department of Cell Biology, Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Yocheved L
authors.initials: YL
authors.lastname: Schindler
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Garske
authors.affiliation: Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Wang
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, Indianapolis, IN 46202, USA.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Firulli
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, Indianapolis, IN 46202, USA.
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Firulli
authors.affiliation: Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
authors.affiliation: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA Developmental Genetics Program and Department of Cell Biology, Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA dyelon@ucsd.edu.
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D004247:DNA / Q000737:chemistry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006321:Heart / Q000196:embryology*; D017403:In Situ Hybridization; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000166:cytology*; D012038:Regeneration; D017386:Sequence Homology, Amino Acid; D019076:Transgenes; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004247:DNA; D029961:Zebrafish Proteins; C410915:hand2 protein, zebrafish
keywords: Cardiac regeneration; First heart field; Hand2; Second heart field; Zebrafish