Journal
GENES & DEVELOPMENT
Volume 31, Issue 13, Pages 1325-1338Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.300400.117
Keywords
cardiac progenitors; cardiac mesoderm specification; heartless; Id proteins; CRISPR/Cas9-mediated quadruple knockout; platform for cardiac disease modeling and drug discovery
Categories
Funding
- National Institutes of Health [R01HL113601, R01HL128072, R01HL130840, R44ES023521, P30 AR06130303, R01AR056712, R01AR052779, F31 AR065923-01]
- Muscular Dystrophy Association [200845]
- Fondation Leducq Transatlantic Alliance
- California Institute for Regenerative Medicine (CIRM) [RC1-000132]
- CIRM post-doctoral training program [TG2-01162]
- [P30 CA030199-30]
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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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