Article abstract

Nature Chemical Biology 4, 33 - 41 (2007)
Published online: 18 November 2007 | doi:10.1038/nchembio.2007.54

Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Paul B Yu1,2,6, Charles C Hong1,5,6, Chetana Sachidanandan1,6, Jodie L Babitt3, Donna Y Deng1, Stefan A Hoyng1, Herbert Y Lin3, Kenneth D Bloch1,4 & Randall T Peterson1,2

Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling—dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6–stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.

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  1. Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
  2. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
  3. Program in Membrane Biology and Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 165 Cambridge Street, Boston, Massachusetts 02114, USA.
  4. Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA.
  5. Present address: Division of Cardiovascular Medicine and Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA.
  6. These authors contributed equally to this work.

Correspondence to: Kenneth D Bloch1,4 e-mail: kdbloch@partners.org

Correspondence to: Randall T Peterson1,2 e-mail: peterson@cvrc.mgh.harvard.edu



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