Yu, P. B. et al. Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat. Chem. Biol. 4, 33-41

Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Nature Chemical Biology (Impact Factor: 13). 11/2007; 4(1):33-41. DOI: 10.1038/nchembio.2007.54


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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Available from: Stefan A Hoyng, Apr 14, 2014
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    • "RESEARCH ARTICLE Development (2015) 142, 2352-2363 doi:10.1242/dev.118679 DEVELOPMENT In HAECs, BMP inhibition was achieved through chronic treatment with recombinant Noggin protein, a potent secreted BMP antagonist, or with the pharmacological BMP pathway inhibitor dorsomorphin (Yu et al., 2008). We first verified that Noggin could suppress BMP-induced SMAD1/5 phosphorylation and nuclear translocation (supplementary material Fig. S3A,B). "
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    ABSTRACT: Despite the importance of mucociliary epithelia in animal physiology, the mechanisms controlling their establishment are poorly understood. Using the developing Xenopus epidermis and regenerating human upper airways, we reveal the importance of BMP signalling for the construction of vertebrate mucociliary epithelia. In Xenopus, attenuation of BMP activity is necessary for the specification of multiciliated cells (MCCs), ionocytes and small secretory cells (SSCs). Conversely, BMP activity is required for the proper differentiation of goblet cells. Our data suggest that the BMP and Notch pathways interact to control fate choices in the developing epidermis. Unexpectedly, BMP activity is also necessary for the insertion of MCCs, ionocytes and SSCs into the surface epithelium. In human, BMP inhibition also strongly stimulates the formation of MCCs in normal and pathological (cystic fibrosis) airway samples, whereas BMP overactivation has the opposite effect. This work identifies the BMP pathway as a key regulator of vertebrate mucociliary epithelium differentiation and morphogenesis. © 2015. Published by The Company of Biologists Ltd.
    Development 06/2015; 142(13). DOI:10.1242/dev.118679 · 6.46 Impact Factor
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    • "Interestingly, functional studies in the direct developing hemichordate S. kowalevskii, echinoderms, and our results in P. flava show that regardless of the source of bmp2/4 expression, the activity of the Bmp pathway in all studied ambulacrarians is always confined to the dorsal ectoderm where it is responsible for the specification of dorsal fates (Duboc et al., 2004; Lapraz et al., 2009b; Lowe et al., 2006). Our attempts to inhibit Bmp signaling using dorsomorphin (Hao et al., 2008; Yu et al., 2008) or Noggin (Bayramov et al., 2011) did not affect either the development of P. flava, nor caused any noticeable changes of pSmad1/5 activation (data not shown). Nonetheless, taken together our above-described results strongly suggest that Bmp signaling is involved in patterning dorsal structures during P. flava development. "
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    ABSTRACT: Nodal signaling plays crucial roles in vertebrate developmental processes such as endoderm and mesoderm formation, and axial patterning events along the anteroposterior, dorsoventral and left-right axes. In echinoderms, Nodal plays an essential role in the establishment of the dorsoventral axis and left-right asymmetry, but not in endoderm or mesoderm induction. In protostomes, Nodal signaling appears to be involved only in establishing left-right asymmetry. Hence, it is hypothesized that Nodal signaling has been co-opted to pattern the dorsoventral axis of deuterostomes and for endoderm, mesoderm formation as well as anteroposterior patterning in chordates. Hemichordata, together with echinoderms, represent the sister taxon to chordates. In this study, we analyze the role of Nodal signaling in the indirect developing hemichordate Ptychodera flava. In particular, we show that during gastrulation nodal transcripts are detected in a ring of cells at the vegetal pole that gives rise to endomesoderm and in the ventral ectoderm at later stages of development. Inhibition of Nodal function disrupts dorsoventral fates and also blocks formation of the larval mesoderm. Interestingly, molecular analysis reveals that only mesodermal, apical and ventral gene expression is affected while the dorsal side appears to be patterned correctly. Taken together, this study suggests that the co-option of Nodal signaling in mesoderm formation and potentially in anteroposterior patterning has occurred prior to the emergence of chordates and that Nodal signaling on the ventral side is uncoupled from BMP signaling on the dorsal side, representing a major difference from the molecular mechanisms of dorsoventral patterning events in echinoderms. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 05/2015; 4(7). DOI:10.1242/bio.011809 · 2.42 Impact Factor
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    • "As was the case for FGF2, these FGF9-mediated processes were inhibited by noggin, demonstrating a similar requirement for endogenous BMP signaling. Normalized to total ERK, fold activation of ERK in response to FGF9 dropped from 3.3× (±0.6) in the Next we inhibited BMP signaling at the level of BMP receptors using dorsomorphin, a selective small-molecule inhibitor of ligand-activated type I BMP receptors (BMPRs; Yu et al., 2008; Kamaid et al., 2010). We confirmed that a 30-min preincubation with 5 μM dorsomorphin completely blocked BMP4 from activating its downstream effectors Smad1/5 in DCDMLs but did not FIGURE 1: "
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    ABSTRACT: Fibroblast growth factors (FGFs) play a central role in two processes essential for lens transparency, lens fiber cell differentiation and gap junction-mediated intercellular communication (GJIC). Using serum-free primary cultures of chick lens epithelial cells (DCDMLs), we have investigated how the FGF and bone morphogenetic protein (BMP) signaling pathways positively cooperate to regulate lens development and function. We found that culturing DCDMLs for six days with the BMP blocker noggin inhibits the canonical FGF-to-ERK pathway upstream of FRS2 activation and also prevents FGF from stimulating FRS2- and ERK- independent gene expression, indicating that BMP signaling is required at the level of FGF receptors. Other experiments revealed a second type of BMP/FGF interaction by which FGF promotes expression of BMP target genes as well as of BMP4. Together, these studies reveal a novel mode of cooperation between the FGF and BMP pathways in which BMP keeps lens cells in an optimally FGF-responsive state and, reciprocally, FGF enhances BMP-mediated gene expression. This interaction provides a mechanistic explanation for why disruption of either FGF or BMP signaling in the lens leads to defects in lens development and function. © 2015 by The American Society for Cell Biology.
    Molecular biology of the cell 05/2015; 26(13). DOI:10.1091/mbc.E15-02-0117 · 4.47 Impact Factor
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