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Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca2+ channel

Nature volume 466, pages 874–878 (2010)Cite this article

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Abstract

Electrical gradients are critical for many biological processes, including the normal function of excitable tissues, left–right patterning, organogenesis and wound healing1,2,3,4. The fundamental mechanisms that regulate the establishment and maintenance of such electrical polarities are poorly understood. Here we identify a gradient of electrical coupling across the developing ventricular myocardium using high-speed optical mapping of transmembrane potentials and calcium concentrations in the zebrafish heart. We excluded a role for differences in cellular excitability, connexin localization, tissue geometry and mechanical inputs, but in contrast we were able to demonstrate that non-canonical Wnt11 signals are required for the genesis of this myocardial electrical gradient. Although the traditional planar cell polarity pathway is not involved, we obtained evidence that Wnt11 acts to set up this gradient of electrical coupling through effects on transmembrane Ca2+ conductance mediated by the L-type calcium channel. These data reveal a previously unrecognized role for Wnt/Ca2+ signalling in establishing an electrical gradient in the plane of the developing cardiac epithelium through modulation of ion-channel function. The regulation of cellular coupling through such mechanisms may be a general property of non-canonical Wnt signals.

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Figure 1: Formation of a myocardial electrical gradient in the developing zebrafish ventricle.
Figure 2: Loss of Wnt11 prevents myocardial electrical gradient formation.
Figure 3: Wnt11 regulates Ca 2+ transient amplitudes in cardiomyocytes.
Figure 4: Wnt11 patterns electrical coupling through effects on transmembrane Ca 2+ conductance.

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Acknowledgements

We thank C. P. Heisenberg, L. Solnica-Krezel and J. Mably for the gift of reagents. We thank R. Peterson and I. Drummond for comments on the manuscript. D.P. is supported by a fellowship from the HFSP. A.A.W. was supported by an NIH training award to the CVRC at MGH. C.A.M. is supported by the March of Dimes and the NIH.

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Author notes

  1. Daniela Panáková and Andreas A. Werdich: These authors contributed equally to this work.

Authors and Affiliations

  1. Cardiovascular Division, Brigham and Women’s Hospital/Harvard Medical School, 75 Francis Street, Thorn 11, Boston, Massachusetts 02115, USA,

    Daniela Panáková, Andreas A. Werdich & Calum A. MacRae

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  1. Daniela Panáková
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  2. Andreas A. Werdich
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  3. Calum A. MacRae
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Contributions

D.P. designed and performed the genetic, immunohistochemical and optical mapping experiments; A.A.W. devised techniques for optical voltage mapping and ratiometric Ca2+ imaging, developed analysis software, and designed and performed the corresponding experiments; C.A.M. designed the experimental strategy. D.P., A.A.W. and C.A.M. analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Calum A. MacRae.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-7 with legends. (PDF 443 kb)

Supplementary Movie 1

This movie shows the action potential propagation in wild type linear heart tube at 24 hpf. Action potential propagation is slow and homogeneous. (MOV 9122 kb)

Supplementary Movie 2

This movie shows the action potential propagation in wild type heart at 72 hpf, after looping is complete. (MOV 3892 kb)

Supplementary Movie 3

This movie shows the action potential propagation in a heart from Wnt11 morphant embryos at 72 hpf. (MOV 2855 kb)

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Panáková, D., Werdich, A. & MacRae, C. Wnt11 patterns a myocardial electrical gradient through regulation of the L-type Ca2+ channel. Nature 466, 874–878 (2010). https://doi.org/10.1038/nature09249

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