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ZFIN ID: ZDB-PUB-071125-25
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
Yu, P.B., Hong, C.C., Sachidanandan, C., Babitt, J.L., Deng, D.Y., Hoyng, S.A., Lin, H.Y., Bloch, K.D., and Peterson, R.T.
Date: 2008
Source: Nature Chemical Biology   4(1): 33-41 (Journal)
Registered Authors: Hong, Charles, Peterson, Randall, Sachidanandan, Chetana
Keywords: none
MeSH Terms:
  • Animals
  • Antimicrobial Cationic Peptides/genetics
  • Bone Morphogenetic Protein Receptors, Type I/antagonists & inhibitors
  • Bone Morphogenetic Proteins/antagonists & inhibitors*
  • Bone Morphogenetic Proteins/metabolism
  • Cell Differentiation/drug effects
  • Cell Line, Tumor
  • Hepcidins
  • Iron/blood
  • Iron/metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts/cytology
  • Osteoblasts/drug effects
  • Osteogenesis/drug effects*
  • Phosphorylation
  • Pyrazoles/pharmacology*
  • Pyrimidines/pharmacology*
  • Signal Transduction
  • Smad Proteins/metabolism
  • Small Molecule Libraries/pharmacology*
  • Transcription, Genetic/drug effects
  • Zebrafish*/embryology
  • Zebrafish*/metabolism
PubMed: 18026094 Full text @ Nat. Chem. Biol.
FIGURES
ABSTRACT
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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