Control of cardiac jelly dynamics by NOTCH1 and NRG1 defines the building plan for trabeculation

Gonzalo del Monte-Nieto, Mirana Ramialison, Arne A.S. Adam, Bingruo Wu, Alla Aharonov, Gabriele D’uva, Lauren M. Bourke, Mara E. Pitulescu, Hanying Chen, José Luis de la Pompa, Weinian Shou, Ralf H. Adams, Sarah K. Harten, Eldad Tzahor, Bin Zhou, Richard P. Harvey

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction1. Defective trabeculation leads to embryonic lethality2–4 or non-compaction cardiomyopathy (NCC)5. There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium6, whereas in chicks, chamber wall thickening occurs before overt trabeculation7. In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs2. Endocardium–myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch2,8 and Neuregulin (NRG)4. Late disruption of the Notch pathway causes NCC5. Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice9,10 and the matrix metalloprotease ADAMTS1 promotes trabecular termination3, the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Veg fa, but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease.

Original languageEnglish (US)
Pages (from-to)439-471
Number of pages33
JournalNature
Volume557
Issue number7705
DOIs
StatePublished - Jan 1 2018

ASJC Scopus subject areas

  • General

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