Interplay of cell–cell contacts and RhoA/MRTF‐A signaling regulates cardiomyocyte identity. (15th May 2018)

• Record Type: Journal Article
• Authors: Dorn, Tatjana; Kornherr, Jessica; Parrotta, Elvira I; Zawada, Dorota; Ayetey, Harold; Santamaria, Gianluca; Iop, Laura; Mastantuono, Elisa; Sinnecker, Daniel; Goedel, Alexander; Dirschinger, Ralf J; My, Ilaria; Laue, Svenja; Bozoglu, Tarik; Baarlink, Christian; Ziegler, Tilman; Graf, Elisabeth; Hinkel, Rabea; Cuda, Giovanni; Kääb, Stefan; Grace, Andrew A; Grosse, Robert; Kupatt, Christian; Meitinger, Thomas; Smith, Austin G; Laugwitz, Karl‐Ludwig; Moretti, Alessandra
• Is Part Of: EMBO journal. Volume 37:Number 12(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-05-15
• Subjects: cardiac fat -- cardiac progenitors -- lineage conversion -- MRTF/SRF -- RhoA/ROCK signaling; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201798133
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: In human developing cardiomyocytes cell‐cell contacts at the intercalated disc 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. Cardiomyocytes with pathological ARVC mutations leading to desmosome instability convert into brown/beige adipocytes. RhoA signaling downstream of cell‐cell junctions regulates pathological myocyte‐to‐adipocyte conversion by controlling MRTF‐A cellular localization and PPARγ activation. PPARγ is the master molecular trigger of the cardiomyocyte‐to‐brown/beige fat switch and WT1 acts as co‐regulator. Cardiac fat and a subpopulation of CMs share common embryonic Isl1/Wt1 expressing progenitors. Abstract : Stable desmosomes prevent pathological myocyte‐to‐adipocyte conversion resulting from MRTF‐A mislocalization and subsequent PPAR activation.