Id genes are essential for early heart formation
Thomas J. Cunningham1, 10, Michael S. Yu1, 2,10, Wesley L. McKeithan1,3,4,10, Sean Spiering1, Florent Carrette1, Chun-Teng Huang1, Paul J. Bushway2, Matthew Tierney1, Sonia Albini1, Mauro Giacca5, Miguel Mano6, Pier Lorenzo Puri1,7, Alessandra Sacco1, Pilar Ruiz-Lozano1,8, Jean-Francois Riou9, Muriel Umbhauer9, Gregg Duester1, Mark Mercola1,4,11 and Alexandre R. Colas1, 11
- Author Affiliations
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, 92037, USA;
2Department of Bioengineering, University of California at San Diego, La Jolla, California 92037, USA;
3Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037, USA;
4Department of Medicine and Cardiovascular Institute, Stanford University, Palo Alto, California 94305, USA;
5International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy;
6Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal;
7Istituti di Ricovero e Cura a Carattere Scientifico, Fondazione Santa Lucia, 00179 Rome, Italy;
8Regencor, Inc., Los Altos, California 94022, USA;
9UMR 7622 Developmental Biology, Sorbonne Universités, University Pierre and Marie Curie, F- 75005 Paris, France
Corresponding author: acolas@sbpdiscovery.org
↵10 These authors contributed equally to this work.
↵11 These authors contributed equally to this work.
Abstract
Deciphering the fundamental mechanisms controlling cardiac specification is critical for our understanding of how heart formation is initiated during embryonic development and for applying stem cell biology to regenerative medicine and disease modeling. Using systematic and unbiased functional screening approaches, we discovered that the Id family of helix–loop–helix proteins is both necessary and sufficient to direct cardiac mesoderm formation in frog embryos and human embryonic stem cells. Mechanistically, Id proteins specify cardiac cell fate by repressing two inhibitors of cardiogenic mesoderm formation —Tcf3 and Foxa2—and activating inducers Evx1, Grrp1, and Mesp1. Most importantly, CRISPR/Cas9-mediated ablation of the entire Id (Id1–4) family in mouse embryos leads to failure of anterior cardiac progenitor specification and the development of heartless embryos. Thus, Id proteins play a central and evolutionarily conserved role during heart formation and provide a novel means to efficiently produce cardiovascular progenitors for regenerative medicine and drug discovery applications.
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Footnotes
Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.300400.117.
Freely available online through the Genes & Development Open Access option.
Received April 12, 2017. Accepted July 17, 2017.
© 2017 Cunningham et al.; Published by Cold Spring Harbor Laboratory Press
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International ), as described at http://creativecommons.org/licenses/by/4.0/.
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