PUBLICATION

Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Authors
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.
ID
ZDB-PUB-071125-25
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.
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.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping