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A role for Smad6 in development and homeostasis of the cardiovascular system

Nature Genetics volume 24, pages 171–174 (2000)Cite this article

Abstract

Smad proteins are intracellular mediators of signalling initiated by Tgf-βsuperfamily ligands (Tgf-βs, activins and bone morphogenetic proteins (Bmps)). Smads 1, 2, 3, 5 and 8 are activated upon phosphorylation by specific type I receptors, and associate with the common partner Smad4 to trigger transcriptional responses1. The inhibitory Smads (6 and 7) are transcriptionally induced in cultured cells treated with Tgf-β superfamily ligands, and downregulate signalling in in vitro assays2,3,4,5,6,7. Gene disruption in mice has begun to reveal specific developmental and physiological functions of the signal-transducing Smads. Here we explore the role of an inhibitory Smad in vivo by targeted mutation of Madh6 (which encodes the Smad6 protein). Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities. Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation. The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants. These defects highlight the importance of Smad6 in the tissue-specific modulation of Tgf-β superfamily signalling pathways in vivo.

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Figure 1: Generation of Madh6-mutant mice.
Figure 2: X-gal staining pattern.
Figure 3: Vascular physiology.
Figure 4: Pathology of Madh6-mutant mice.

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Acknowledgements

We thank M. Nomura and E. Li for help with embryo analysis; V. Kadambi, G. Garcia-Cardeña and R. Breitbart for helpful discussions; Q. Fang and R. Riley for animal care; M. Nieman, R.L. Sutliff and C. Weber for technical contributions; and the help and advice of all our colleagues. This work was supported by Eli Lilly.

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Authors and Affiliations

  1. Millennium Pharmaceuticals, Cambridge, Massachusetts, USA

    Katherine M. Galvin, Michael J. Donovan, Catherine A. Lynch, Ronald I. Meyer, Victoria Fairchild-Huntress, Kristen L. Dixon, Judy H. Dunmore, Dean Falb & Dennis Huszar

  2. Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Richard J. Paul & John N. Lorenz

  3. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Michael A. Gimbrone Jr

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  1. Katherine M. Galvin
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Correspondence to Katherine M. Galvin.

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Galvin, K., Donovan, M., Lynch, C. et al. A role for Smad6 in development and homeostasis of the cardiovascular system. Nat Genet 24, 171–174 (2000). https://doi.org/10.1038/72835

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