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Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors

Nature Medicine volume 8, pages 850–855 (2002)Cite this article

Abstract

Heart septation and valve malformations constitute the most common anatomical birth defects. These structures arise from the endocardial cushions within the atrioventricular canal (AVC) through dynamic interactions between cushion cells and the extracellular matrix (termed cardiac jelly). Transformation of endothelial cells to mesenchymal cells is essential for the proper development of the AVC and subsequent septation and valve formation. Atrioventricular septal defects can result from incomplete endocardial cushion morphogenesis. We show that hyaluronan-deficient AVC explants from Has2−/− embryos, which normally lack mesenchyme formation, are rescued by heregulin treatment, which restores phosphorylation of ErbB2 and ErbB3. These events were blocked using a soluble ErbB3 molecule, as well as with an inhibitor of ErbB2, herstatin. We show further that ErbB3 is activated during hyaluronan treatment of Has2−/− explants. These data provide a link between extracellular matrix-hyaluronan and ErbB receptor activation during development of early heart-valve and septal mesenchyme.

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Figure 1: Detection of ErbB2 within the cushion mesenchyme during AVC morphogenesis.
Figure 2: Cushion mesenchyme is positive for ErbB3.
Figure 3: Receptor profile for ErbB2, ErbB3 and ErbB4 during in vitro AVC morphogenesis.
Figure 4: Deficit in epithelial to mesenchymal transformation (EMT) in ErbB3−/− and ErbB2−/− heart explant cultures.
Figure 5: Rescue of Has2-deficient AVC explants by HRG or HA mediated through ErbB receptor activation.
Figure 6: Full induction of EMT requires HA and activated ErbB2 and ErbB3 during in vitro AVC morphogenesis.

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Acknowledgements

We thank S. Erickson for the ErbB2- and ErbB3-targeted mouse lines; G. Lemke for the ErbB4-targeted mouse line; C. Birchmeier for the Heregulin-targeted mouse line; G. Clinton for the Herstatin plasmid19; N. Maihle and H. Lee for purified soluble p85 ErbB3 protein20; D. Lee and N. Luetteke for critical discussions; A.N. Camenisch for inspirational discussions; M. Ruona for medical graphics support; and C. Williams and S. Fleck for manuscript preparation. This study was supported by the PANDA Foundation.

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Authors and Affiliations

  1. College of Pharmacy and Steele Memorial Children's Research Center, University of Arizona, Tucson, Arizona, USA

    Todd D. Camenisch

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona, USA

    Todd D. Camenisch, Joyce A. Schroeder & Judy Bradley

  3. Department of Pediatrics and Steele Memorial Children's Research Center, University of Arizona School of Medicine, Tucson, Arizona, USA

    Scott E. Klewer

  4. Salt Lake City Veterans Administration Health Care System, and University of Utah, Salt Lake City, Utah, USA

    John A. McDonald

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Correspondence to Todd D. Camenisch.

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Camenisch, T., Schroeder, J., Bradley, J. et al. Heart-valve mesenchyme formation is dependent on hyaluronan-augmented activation of ErbB2–ErbB3 receptors. Nat Med 8, 850–855 (2002). https://doi.org/10.1038/nm742

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