title: Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development.
abstract: Defects in cardiac valve morphogenesis and septation of the heart chambers constitute some of the most common human congenital abnormalities. Some of these defects originate from errors in atrioventricular (AV) endocardial cushion development. Although this process is being extensively studied in mouse and chick, the zebrafish system presents several advantages over these models, including the ability to carry out forward genetic screens and study vertebrate gene function at the single cell level. In this paper, we analyze the cellular and subcellular architecture of the zebrafish heart during stages of AV cushion and valve development and gain an unprecedented level of resolution into this process. We find that endocardial cells in the AV canal differentiate morphologically before the onset of epithelial to mesenchymal transformation, thereby defining a previously unappreciated step during AV valve formation. We use a combination of novel transgenic lines and fluorescent immunohistochemistry to analyze further the role of various genetic (Notch and Calcineurin signaling) and epigenetic (heart function) pathways in this process. In addition, from a large-scale forward genetic screen we identified 55 mutants, defining 48 different genes, that exhibit defects in discrete stages of AV cushion development. This collection of mutants provides a unique set of tools to further our understanding of the genetic basis of cell behavior and differentiation during AV valve development.
authors.affiliation: Department of Biochemistry and Biophysics and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Beis
authors.forename: Thomas
authors.initials: T
authors.lastname: Bartman
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Jin
authors.forename: Ian C
authors.initials: IC
authors.lastname: Scott
authors.forename: Leonard A
authors.initials: LA
authors.lastname: D'Amico
authors.forename: Elke A
authors.initials: EA
authors.lastname: Ober
authors.forename: Heather
authors.initials: H
authors.lastname: Verkade
authors.forename: Julie
authors.initials: J
authors.lastname: Frantsve
authors.forename: Holly A
authors.initials: HA
authors.lastname: Field
authors.forename: Ann
authors.initials: A
authors.lastname: Wehman
authors.forename: Herwig
authors.initials: H
authors.lastname: Baier
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tallafuss
authors.forename: Laure
authors.initials: L
authors.lastname: Bally-Cuif
authors.forename: Jau-Nian
authors.initials: JN
authors.lastname: Chen
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Benno
authors.initials: B
authors.lastname: Jungblut
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D004699:Endocardium / Q000166:cytology / Q000196:embryology*; D005453:Fluorescence; D006351:Heart Valves / Q000196:embryology*; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*
chemical_list: D051880:Receptors, Notch; D019703:Calcineurin