Letter | Published:

Coordinating cardiomyocyte interactions to direct ventricular chamber morphogenesis

Nature volume 534, pages 700704 (30 June 2016) | Download Citation


Many organs are composed of complex tissue walls that are structurally organized to optimize organ function. In particular, the ventricular myocardial wall of the heart comprises an outer compact layer that concentrically encircles the ridge-like inner trabecular layer. Although disruption in the morphogenesis of this myocardial wall can lead to various forms of congenital heart disease1 and non-compaction cardiomyopathies2, it remains unclear how embryonic cardiomyocytes assemble to form ventricular wall layers of appropriate spatial dimensions and myocardial mass. Here we use advanced genetic and imaging tools in zebrafish to reveal an interplay between myocardial Notch and Erbb2 signalling that directs the spatial allocation of myocardial cells to their proper morphological positions in the ventricular wall. Although previous studies have shown that endocardial Notch signalling non-cell-autonomously promotes myocardial trabeculation through Erbb2 and bone morphogenetic protein (BMP) signalling3, we discover that distinct ventricular cardiomyocyte clusters exhibit myocardial Notch activity that cell-autonomously inhibits Erbb2 signalling and prevents cardiomyocyte sprouting and trabeculation. Myocardial-specific Notch inactivation leads to ventricles of reduced size and increased wall thickness because of excessive trabeculae, whereas widespread myocardial Notch activity results in ventricles of increased size with a single-cell-thick wall but no trabeculae. Notably, this myocardial Notch signalling is activated non-cell-autonomously by neighbouring Erbb2-activated cardiomyocytes that sprout and form nascent trabeculae. Thus, these findings support an interactive cellular feedback process that guides the assembly of cardiomyocytes to morphologically create the ventricular myocardial wall and more broadly provide insight into the cellular dynamics of how diverse cell lineages organize to create form.

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We thank N. Tedeschi for fish care; B. Le for experimental assistance; S. Evans, D. Yelon, and Chi laboratory members for comments on the manuscript; N. Ninov and D. Stainier for plasmids; B. Link for the d2GFP BMP and d2GFP Notch reporter lines; N. Lawson for the eGFP Notch reporter line; B. Appel for the myocardial Cerulean line; K. Poss for the myocardial CreER and Brainbow/priZm lines; and W. Talbot for the erbb2 mutant. This work was supported in part by grants from American Heart Association (14POST20380738) to L.Z.; the March of Dimes (1-FY14-327) to R.A.M.; the NIH/NHLBI (5R01HL127067) to C.G.B. and C.E.B.; and the National Institutes of Health to N.C.C.

Author information


  1. Department of Medicine, Division of Cardiology, University of California, San Diego, La Jolla, California 92093, USA

    • Peidong Han
    • , Joshua Bloomekatz
    • , Jie Ren
    • , Ruilin Zhang
    • , Jonathan D. Grinstein
    •  & Neil C. Chi
  2. Cardiovascular Research Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA

    • Long Zhao
    • , C. Geoffrey Burns
    •  & Caroline E. Burns
  3. Center for Diabetes and Metabolic Diseases, Department of Pediatrics and Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

    • Ryan M. Anderson
  4. Institute of Genomic Medicine, University of California, San Diego, La Jolla, California 92093, USA

    • Neil C. Chi


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P.H. and N.C.C. conceived the project and the design of the experimental strategy. P.H., J.R., J.B., R.Z., and J.D.G. conducted experiments. L.Z. generated the ubi:RSdnM transgenic line. P.H. and N.C.C. generated and characterized the myl7:Cre transgenic line. C.E.B., C.G.B., and R.A.M. provided key reagents. P.H., J.B. and N.C.C. prepared the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Neil C. Chi.

Reviewer Information Nature thanks B. G. Bruneau and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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