Resumen de Interplay of cell–cell contacts and RhoA/MRTF‐A signaling regulates cardiomyocyte identity

Tatjana Dorn, Jessica Kornherr, Elvira I Parrotta, Dorota Zawada, Harold Ayetey, Gianluca Santamaria, Laura Iop, Elisa Mastantuono, Daniel Sinnecker, Alexander Goedel, Ralf J Dirschinger, Ilaria My, Svenja Laue, Tarik Bozoglu, Christian Baarlink, Tilman Ziegler, Elisabeth Graf, Rabea Hinkel, Giovanni Cuda, Stefan Kääb, Andrew A Grace, Robert Grosse, Christian Kupatt, Thomas Meitinger, Austin G Smith, Karl-Ludwig Laugwitz, Alessandra Moretti

• Cell–cell and cell–matrix interactions guide organ development and homeostasis by controlling lineage specification and maintenance, but the underlying molecular principles are largely unknown. Here, we show that in human developing cardiomyocytes cell–cell contacts at the intercalated disk connect to remodeling of the actin cytoskeleton by regulating the RhoA‐ROCK signaling to maintain an active MRTF/SRF transcriptional program essential for cardiomyocyte identity. Genetic perturbation of this mechanosensory pathway activates an ectopic fat gene program during cardiomyocyte differentiation, which ultimately primes the cells to switch to the brown/beige adipocyte lineage in response to adipogenesis‐inducing signals. We also demonstrate by in vivo fate mapping and clonal analysis of cardiac progenitors that cardiac fat and a subset of cardiac muscle arise from a common precursor expressing Isl1 and Wt1 during heart development, suggesting related mechanisms of determination between the two lineages.