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First published online 17 August 2005
doi: 10.1242/dev.01970
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1 Department of Biochemistry and Biophysics and Cardiovascular Research
Institute, University of California, San Francisco, San Francisco, CA 94143,
USA
2 Department of Physiology, University of California, San Francisco, San
Francisco, CA 94143, USA
3 Zebrafish Neurogenetics Group, IDG, GSF-National Research Center for
Environment and Health, Ingolstaedter Landstrasse 1, 85764 Neuherberg,
Germany
4 Department of Molecular, Cellular, and Developmental Biology, University of
California Los Angeles, CA 90095, USA
¶ Author for correspondence (didier_stainier{at}biochem.ucsf.edu)
Accepted 7 July 2005
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.
Key words: Heart, AV canal, Endocardium, Notch, Calcineurin, Zebrafish
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