Notch1/Nrg1 control of cardiac jelly dynamics defines the building plan for trabeculation

del Monte-Nieto G1, Ramialison M2, Adam AAS1, Wu B3, Aharonov A4, Bourke LM5, Harten SK5, Tzahor E4, Zhou B3 and Harvey RP1

  1. Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
  2. Australian Regenerative Medicine Institute. Monash University, Victoria 3800, Australia.
  3. Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
  4. Weizmann Institute of Science, Rehovot 7610001, Israel.
  5. QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia.

In vertebrate hearts, ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes critical for efficient cardiac contraction in the early embryo, and for ventricular conduction, septation, and wall thickening through the process of compaction in the foetal heart. Defective trabeculation at early developmental stages leads to embryonic lethality whereas defects at later stages can lead to Non-Compaction Cardiomyopathy, the third most commonly diagnosed cardiomyopathy in adults. There are divergent views on when and how trabeculation is initiated in different species. In mice, the onset of trabeculation has not been formally addressed, but is proposed to begin at embryonic day (E)9.0 as cardiomyocytes form radially-oriented ribs. Endocardium-myocardium communication is essential for trabeculation, with numerous signalling pathways identified, including Neuregulin1 (Nrg1) and Notch1. Late disruption of the Notch1 pathway causes Non-Compaction Cardiomyopathy. Although mutants in cardiac jelly extracellular matrix (ECM) genes Has2 and Vcan lack trabeculae, and matrix metalloprotease ADAMTS1 activity at E14.5 promotes total cardiac jelly degradation and trabecular growth arrest, the role of ECM dynamics and its molecular regulation during early trabeculation is poorly understood. Here we present a new model of cardiac trabeculation starting as early as the heart tube forms (E8.0), integrating for the first time dynamic endocardial and myocardial cell behaviours, and ECM remodelling, and revealing new epistatic relationships for known signalling pathways. Notch1 signalling promotes ECM degradation during formation of endocardial projections critical for individualization of trabecular units, while Nrg1 promotes myocardial ECM synthesis, necessary for trabecular rearrangement and growth. These systems interconnect through Nrg1 control of Vegfa, yet act antagonistically to establish trabecular architecture. Furthermore, these insights allowed the prediction of persistent cardiac jelly and trabecular growth as a potential cause of disease in a murine Non-Compaction Cardiomyopathy model, providing new understanding of congenital heart disease pathophysiology.