A role for Smad6 in development and homeostasis of the cardiovascular system (original) (raw)
- Letter
- Published: February 2000
- 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 Huszar1
Nature Genetics volume 24, pages 171–174 (2000)Cite this article
- 2537 Accesses
- 393 Citations
- Metrics details
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Massague, J. TGF-β signal transduction. Annu. Rev. Biochem. 67, 753–791 (1998).
Article CAS Google Scholar - Afrakhte, M. et al. Induction of inhibitory Smad6 and Smad7 mRNA by TGF-β family members. Biochem. Biophys. Res. Commun. 249, 505–511 (1998).
Article CAS Google Scholar - Hata, A., Lagna, G., Massague, J. & Hemmati-Brivanlou, A. Smad6 inhibits BMP/Smad1 signaling by specifically competing with the Smad4 tumor suppressor. Genes Dev. 12, 186–197 (1998).
Article CAS Google Scholar - Imamura, T. et al. Smad6 inhibits signalling by the TGF-β superfamily. Nature 389, 622–626 (1997).
Article CAS Google Scholar - Ishisaki, A. et al. Differential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cells. J. Biol. Chem. 274, 13637–13642 (1999).
Article CAS Google Scholar - Takase, M. et al. Induction of Smad6 mRNA by bone morphogenetic proteins. Biochem. Biophys. Res. Commun. 244, 26–29 (1998).
Article CAS Google Scholar - Topper, J.N. et al. Vascular MADs: two novel MAD-related genes selectively inducible by flow in human vascular endothelium. Proc. Natl Acad. Sci. USA 94, 9314–9319 (1997).
Article CAS Google Scholar - Cohen, R.A., Zitnay, K.M., Weisbrod, R.M. & Tesfamariam, B. Influence of the endothelium on tone and the response of isolated pig coronary artery to norepinephrine. J. Pharmacol. Exp. Ther. 244, 550–555 (1988).
CAS PubMed Google Scholar - Huang, J.X., Potts, J.D., Vincent, E.B., Weeks, D.L. & Runyan, R.B. Mechanisms of cell transformation in the embryonic heart. Ann. NY Acad. Sci. 752, 317–330 (1995).
Article CAS Google Scholar - Reddi, A.H. Bone and cartilage differentiation. Curr. Opin. Genet. Dev. 4, 737–744 (1994).
Article CAS Google Scholar - Bostrom, K., Watson, K.E., Stanford, W.P. & Demer, L.L. Atherosclerotic calcification: relation to developmental osteogenesis. Am. J. Cardiol. 75, 88B–91B (1995).
Article CAS Google Scholar - Brown, C.B., Boyer, A.S., Runyan, R.B. & Barnett, J.V. Requirement of type III TGF-β receptor for endocardial cell transformation in the heart. Science 283, 2080–2082 (1999).
Article CAS Google Scholar - Marchuk, D.A. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr. Opin. Hematol. 5, 332–338 (1998).
Article CAS Google Scholar - Moore, C.S., Mjaatvedt, C.H. & Gearhart, J.D. Expression and function of activin β A during mouse cardiac cushion tissue formation. Dev. Dyn. 212, 548–562 (1998).
Article CAS Google Scholar - Perrella, M.A., Jain, M.K. & Lee, M.E. Role of TGF-β in vascular development and vascular reactivity. Miner. Electrolyte Metab. 24, 136–143 (1998).
Article CAS Google Scholar - Dudley, A.T. & Robertson, E.J. Overlapping expression domains of bone morphogenetic protein family members potentially account for limited tissue defects in BMP7 deficient embryos. Dev. Dyn. 208, 349–362 (1997).
Article CAS Google Scholar - Millan, F.A., Denhez, F., Kondaiah, P. & Akhurst, R.J. Embryonic gene expression patterns of TGF β 1, β 2 and β 3 suggest different developmental functions in vivo. Development 111, 131–143 (1991).
CAS PubMed Google Scholar - Mercer, E.H., Hoyle, G.W., Kapur, R.P., Brinster, R.L. & Palmiter, R.D. The dopamine β-hydroxylase gene promoter directs expression of E. coli lacZ to sympathetic and other neurons in adult transgenic mice. Neuron 7, 703–716 (1991).
Article CAS Google Scholar - McBurney, M.W. et al. The mouse Pgk-1 gene promoter contains an upstream activator sequence. Nucleic Acids Res. 19, 5755–5761 (1991).
Article CAS Google Scholar - Bradley, A. in Teratocarcinomas and Embryonic Stem Cells: A Practical Approach (ed. Robertson, E.J.) (IRL, Oxford, 1987).
Google Scholar - Bonnerot, C.N. & Nicolas, J.-F in Methods in Enzymology 225: Guide to Techniques in Mouse Development (eds Wassarman, P.M. & DePamphilis, M.L.) 451–472 (Academic, San Diego, 1993).
Book Google Scholar - Lalli, J., Harrer, J., Luo, W., Kranias, E.G. & Paul, R.J. Targeted ablation of the phospholamban gene is associated with a marked decrease in sensitivity in aortic smooth muscle. Circ. Res. 80, 506–513 (1997).
Article CAS Google Scholar
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.
Author information
Authors and Affiliations
- 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 - Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
Richard J. Paul & John N. Lorenz - Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Michael A. Gimbrone Jr
Authors
- Katherine M. Galvin
You can also search for this author inPubMed Google Scholar - Michael J. Donovan
You can also search for this author inPubMed Google Scholar - Catherine A. Lynch
You can also search for this author inPubMed Google Scholar - Ronald I. Meyer
You can also search for this author inPubMed Google Scholar - Richard J. Paul
You can also search for this author inPubMed Google Scholar - John N. Lorenz
You can also search for this author inPubMed Google Scholar - Victoria Fairchild-Huntress
You can also search for this author inPubMed Google Scholar - Kristen L. Dixon
You can also search for this author inPubMed Google Scholar - Judy H. Dunmore
You can also search for this author inPubMed Google Scholar - Michael A. Gimbrone Jr
You can also search for this author inPubMed Google Scholar - Dean Falb
You can also search for this author inPubMed Google Scholar - Dennis Huszar
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toKatherine M. Galvin.
Rights and permissions
About this article
Cite this article
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
- Received: 12 August 1999
- Accepted: 08 December 1999
- Issue Date: February 2000
- DOI: https://doi.org/10.1038/72835