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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    • "RESEARCH ARTICLE Biology Open (2015) 000, 1–11 doi:10.1242/bio.20149977 lowered Smad2 activity, so we used dorsomorphin at 20 mM, (Fig. 5B, lane 3; Yu et al., 2008). Treatment with 100 mM SB43 and 20 mM DM (SB43+DM) was sufficient to repress both pSmad1/5/8 and pSmad2 (3.061.7%, "
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    ABSTRACT: Retina formation requires the correct spatiotemporal patterning of key regulatory factors. While it is known that repression of several signaling pathways lead to specification of retinal fates, addition of only Noggin, a known BMP antagonist, can convert pluripotent Xenopus laevis animal cap cells to functional retinal cells. The aim of this study is to determine the intracellular molecular events that occur during this conversion. Surprisingly, blocking BMP signaling alone failed to mimic Noggin treatment. Overexpressing Noggin in pluripotent cells resulted in a concentration-dependent suppression of both Smad1 and Smad2 phosphorylation, which act downstream of BMP and Activin signaling, respectively. This caused a decrease in downstream targets: endothelial marker, xk81, and mesodermal marker, xbra. We treated pluripotent cells with dominant-negative receptors or the chemical inhibitors, dorsomorphin and SB431542, which each target either the BMP or Activin signaling pathway. We determined the effect of these treatments on retina formation using the Animal Cap Transplant (ACT) assay; in which treated pluripotent cells were transplanted into the eye field of host embryos. We found that inhibition of Activin signaling, in the presence of BMP signaling inhibition, promotes efficient retinal specification in Xenopus tissue, mimicking the affect of adding Noggin alone. In whole embryos, we found that the eye field marker, rax, expanded when adding both dominant-negative Smad1 and Smad2, as did treating the cells with both dorsomorphin and SB431542. Future studies could translate these findings to a mammalian culture assay, in order to more efficiently produce retinal cells in culture. © 2015. Published by The Company of Biologists Ltd.
    Biology Open 03/2015; 4(4). DOI:10.1242/bio.20149977 · 2.42 Impact Factor
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