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EMBO J. 2018 May 15. pii: e98133. doi: 10.15252/embj.201798133. [Epub ahead of print]

Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity.

Author information

1
Klinik und Poliklinik Innere Medizin I, Klinikum rechts der Isar - Technical University of Munich, Munich, Germany.
2
Department of Experimental and Clinical Medicine, Medical School, University of Magna Grecia, Catanzaro, Italy.
3
Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
4
Papworth Hospital NHS Foundation Trust, Cambridge, UK.
5
Institute of Human Genetics, Klinikum rechts der Isar - Technical University of Munich, Munich, Germany.
6
DZHK (German Centre for Cardiovascular Research) - partner site Munich Heart Alliance, Munich, Germany.
7
Pharmacology Institute, Philipps University Marburg, Marburg, Germany.
8
IPEK Institute for Cardiovascular Prevention, Klinikum der Universität München - Ludwig-Maximillians-Universität, Munich, Germany.
9
Medizinische Klinik und Poliklinik I, Klinikum der Universität München - Ludwig-Maximillians-Universität, Munich, Germany.
10
Department of Biochemistry, University of Cambridge, Cambridge, UK.
11
Klinik und Poliklinik Innere Medizin I, Klinikum rechts der Isar - Technical University of Munich, Munich, Germany laugwitz@mytum.de amoretti@mytum.de.

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.

KEYWORDS:

MRTF/SRF; RhoA/ROCK signaling; cardiac fat; cardiac progenitors; lineage conversion

PMID:
29764980
DOI:
10.15252/embj.201798133
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