Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling
- Claudio Cantù1,6,8,
- Anastasia Felker1,8,
- Dario Zimmerli1,8,
- Karin D. Prummel1,
- Elena M. Cabello1,
- Elena Chiavacci1,7,
- Kevin M. Méndez-Acevedo2,
- Lucia Kirchgeorg1,
- Sibylle Burger1,
- Jorge Ripoll3,
- Tomas Valenta1,
- George Hausmann1,
- Nathalie Vilain4,
- Michel Aguet4,
- Alexa Burger1,
- Daniela Panáková2,5,
- Konrad Basler1 and
- Christian Mosimann1
- 1Institute of Molecular Life Sciences, University of Zürich, 8057 Zürich, Switzerland;
- 2Electrochemical Signaling in Development and Disease, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin-Buch, Germany;
- 3Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid, 28911 Madrid, Spain;
- 4Swiss Institute for Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland;
- 5Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Berlin, 10115 Berlin, Germany
- Corresponding authors: christian.mosimann{at}imls.uzh.ch, kb{at}imls.uzh.ch
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↵8 These authors contributed equally to this work.
Abstract
Bcl9 and Pygopus (Pygo) are obligate Wnt/β-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, β-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the β-catenin–BCL9–Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective β-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.315531.118.
- Received April 10, 2018.
- Accepted August 22, 2018.
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