Dorsomorphin Inhibits BMP Signals Required for Embryogenesis and Iron Metabolism

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2007 Nov 21

PMID 18026094

Citations 532

Authors

Paul B Yu

Charles C Hong

Chetana Sachidanandan

Jodie L Babitt

Donna Y Deng

Stefan A Hoyng

Herbert Y Lin

Kenneth D Bloch

Randall T Peterson

Affiliations

Soon will be listed here.

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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