Hox-dependent coordination of mouse cardiac progenitor cell patterning and differentiation
Sonia Stefanovic, Brigitte Laforest, Jean‐Pierre Desvignes, Fabienne Lescroart, Laurent Argiro, Corinne Maurel-Zaffran, David Salgado, Elise Plaindoux, Christopher De Bono, Kristijan Pažur, Magali Théveniau‐Ruissy, Christophe Béroud, Michel Pucéat, Anthony Gavalas, Robert G. Kelly, Stéphane Zaffran
Abstract
Perturbation of addition of second heart field (SHF) cardiac progenitor cells to the poles of the heart tube results in congenital heart defects (CHD). The transcriptional programs and upstream regulatory events operating in different subpopulations of the SHF remain unclear. Here, we profile the transcriptome and chromatin accessibility of anterior and posterior SHF sub-populations at genome-wide levels and demonstrate that Hoxb1 negatively regulates differentiation in the posterior SHF. Spatial mis-expression of Hoxb1 in the anterior SHF results in hypoplastic right ventricle. Activation of Hoxb1 in embryonic stem cells arrests cardiac differentiation, whereas Hoxb1 -deficient mouse embryos display premature cardiac differentiation. Moreover, ectopic differentiation in the posterior SHF of embryos lacking both Hoxb1 and its paralog Hoxa1 results in atrioventricular septal defects. Our results show that Hoxb1 plays a key role in patterning cardiac progenitor cells that contribute to both cardiac poles and provide new insights into the pathogenesis of CHD.