Nature Genetics
24, 171 - 174 (2000)
doi:10.1038/72835
A role for Smad6 in development and homeostasis of the cardiovascular systemKatherine M. Galvin1, Michael J. Donovan1, Catherine A. Lynch1, Ronald I. Meyer1, Richard J. Paul2, John N. Lorenz2, Victoria Fairchild-Huntress1, Kristen L. Dixon1, Judy H. Dunmore1, Michael A. Gimbrone Jr3, Dean Falb1
& Dennis Huszar11
Millennium Pharmaceuticals, Cambridge, Massachusetts, USA. 2
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 3
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Correspondence should be addressed to Katherine M. Galvin galvin@mpi.comSmad proteins are intracellular mediators of signalling initiated by Tgf- superfamily ligands (Tgf-s, 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- 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- superfamily signalling pathways in vivo.
|
