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A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.

Kelley R, Ren R, Pi X, Wu Y, Moreno I, Willis M, Moser M, Ross M, Podkowa M, Attisano L, Patterson C - J. Cell Biol. (2009)

Bottom Line: Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling.This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation.This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

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Related in: MedlinePlus

Bmper inhibits Bmp signaling during lung development. Lung development and Bmp4 activity were evaluated in wild-type (WT) mice versus mice with a heterozygous (HT) inactivation of Bmper at postnatal day 0. (a) Hematoxylin and eosin analysis of heterozygous lungs demonstrated delayed branching morphogenesis and inadequate expanded alveoli, which were separated by expansive interstitial mesenchyme. (b) Staining for the type II epithelial cell marker prosurfactant C (arrows). Bars, 100 µM. Positive staining is brown and counterstaining is blue. Graphical representation of the percentage of prosurfactant C–positive cells in wild-type versus Bmper het lungs. (c) Id1 mRNA expression was measured as a target of downstream Bmp activity by PCR. (d) Representative blots of endogenous Bmp4 in lysates (postnatal day 0) of lung for two individual animals each of wild-type, heterozygous, and knockout (KO) Bmper mice.
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fig7: Bmper inhibits Bmp signaling during lung development. Lung development and Bmp4 activity were evaluated in wild-type (WT) mice versus mice with a heterozygous (HT) inactivation of Bmper at postnatal day 0. (a) Hematoxylin and eosin analysis of heterozygous lungs demonstrated delayed branching morphogenesis and inadequate expanded alveoli, which were separated by expansive interstitial mesenchyme. (b) Staining for the type II epithelial cell marker prosurfactant C (arrows). Bars, 100 µM. Positive staining is brown and counterstaining is blue. Graphical representation of the percentage of prosurfactant C–positive cells in wild-type versus Bmper het lungs. (c) Id1 mRNA expression was measured as a target of downstream Bmp activity by PCR. (d) Representative blots of endogenous Bmp4 in lysates (postnatal day 0) of lung for two individual animals each of wild-type, heterozygous, and knockout (KO) Bmper mice.

Mentions: Bmper mice died at birth (similar to the findings of Ikeya et al., 2006), whereas heterozygotes survived. Both Bmper +/− and Bmper −/− mice exhibited widespread tissue-specific defects during embryonic development. Given the important role of Bmp4 signaling in lung development and our findings that Bmp4 and Bmper share a concentration-dependent relationship in the regulation of lung MEF survival we were particularly interested in examining the structural defects in the lungs of Bmper-deficient mice. In the perinatal lung of Bmper +/− mice, an overgrowth of mesenchymal cells (which normally express Bmper) appeared to prevent complete alveoli expansion, as indicated by smaller and fewer terminal sacs that were separated by thickened interstitial mesenchyme (Fig. 7 a). These anatomical defects are similar to lung phenotypes reported previously in Bmper-deficient mice (Ikeya et al., 2006).


A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.

Kelley R, Ren R, Pi X, Wu Y, Moreno I, Willis M, Moser M, Ross M, Podkowa M, Attisano L, Patterson C - J. Cell Biol. (2009)

Bmper inhibits Bmp signaling during lung development. Lung development and Bmp4 activity were evaluated in wild-type (WT) mice versus mice with a heterozygous (HT) inactivation of Bmper at postnatal day 0. (a) Hematoxylin and eosin analysis of heterozygous lungs demonstrated delayed branching morphogenesis and inadequate expanded alveoli, which were separated by expansive interstitial mesenchyme. (b) Staining for the type II epithelial cell marker prosurfactant C (arrows). Bars, 100 µM. Positive staining is brown and counterstaining is blue. Graphical representation of the percentage of prosurfactant C–positive cells in wild-type versus Bmper het lungs. (c) Id1 mRNA expression was measured as a target of downstream Bmp activity by PCR. (d) Representative blots of endogenous Bmp4 in lysates (postnatal day 0) of lung for two individual animals each of wild-type, heterozygous, and knockout (KO) Bmper mice.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2654123&req=5

fig7: Bmper inhibits Bmp signaling during lung development. Lung development and Bmp4 activity were evaluated in wild-type (WT) mice versus mice with a heterozygous (HT) inactivation of Bmper at postnatal day 0. (a) Hematoxylin and eosin analysis of heterozygous lungs demonstrated delayed branching morphogenesis and inadequate expanded alveoli, which were separated by expansive interstitial mesenchyme. (b) Staining for the type II epithelial cell marker prosurfactant C (arrows). Bars, 100 µM. Positive staining is brown and counterstaining is blue. Graphical representation of the percentage of prosurfactant C–positive cells in wild-type versus Bmper het lungs. (c) Id1 mRNA expression was measured as a target of downstream Bmp activity by PCR. (d) Representative blots of endogenous Bmp4 in lysates (postnatal day 0) of lung for two individual animals each of wild-type, heterozygous, and knockout (KO) Bmper mice.
Mentions: Bmper mice died at birth (similar to the findings of Ikeya et al., 2006), whereas heterozygotes survived. Both Bmper +/− and Bmper −/− mice exhibited widespread tissue-specific defects during embryonic development. Given the important role of Bmp4 signaling in lung development and our findings that Bmp4 and Bmper share a concentration-dependent relationship in the regulation of lung MEF survival we were particularly interested in examining the structural defects in the lungs of Bmper-deficient mice. In the perinatal lung of Bmper +/− mice, an overgrowth of mesenchymal cells (which normally express Bmper) appeared to prevent complete alveoli expansion, as indicated by smaller and fewer terminal sacs that were separated by thickened interstitial mesenchyme (Fig. 7 a). These anatomical defects are similar to lung phenotypes reported previously in Bmper-deficient mice (Ikeya et al., 2006).

Bottom Line: Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling.This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation.This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC 27599, USA.

ABSTRACT
Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.

Show MeSH
Related in: MedlinePlus