Xenopus mothers against decapentaplegic is an embryonic ventralizing agent that acts downstream of the BMP-2/4 receptor

Development ◽  
1996 ◽  
Vol 122 (8) ◽  
pp. 2359-2366 ◽  
Author(s):  
G.H. Thomsen
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathway ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Tgf Beta ◽  
Cell Fates ◽  
Axial Patterning ◽  
Morphogenetic Protein ◽  
Receptor Signal ◽  
Vertebrate Embryos

Dorsal-ventral patterning in vertebrate embryos is regulated by members of the TGF-beta family of growth and differentiation factors. In Xenopus the activins and Vg1 are potent dorsal mesoderm inducers while members of the bone morphogenetic protein (BMP) subclass pattern ventral mesoderm and regulate ectodermal cell fates. Receptors for ligands in the TGF-beta superfamily are serine-threonine kinases, but little is known about the components of the signal transduction pathway leading away from these receptors. In Drosophila the decapentaplegic protein (dpp), a homolog of vertebrate BMP-2 and BMP-4, functions in dorsal-ventral axial patterning, and a genetic screen for components involved in signaling by dpp has identified a gene named mothers against decapentaplegic (Mad). Mad encodes a unique, predicted cytoplasmic, protein containing no readily identified functional motifs. This report demonstrates that a gene closely related to Drosophila Mad exists in Xenopus (called XMad) and it exhibits activities consistent with a role in BMP signaling. XMad protein induces ventral mesoderm when overexpressed in isolated animal caps and it ventralizes embryos. Furthermore, XMad rescues phenotypes generated by a signaling-defective, dominant-negative, BMP-2/4 receptor. These results furnish evidence that XMad protein participates in vertebrate embryonic dorsal-ventral patterning by functioning in BMP-2/4 receptor signal transduction.

Hemojuvelin Acts as a Bone Morphogenetic Protein Co-Receptor To Regulate Hepcidin Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 511-511 ◽  
Author(s):  
Franklin W. Huang ◽  
Jodie L. Babitt ◽  
Diedra M. Wrighting ◽  
Tarek A. Samad ◽  
Yin Xia ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Bone Morphogenetic Protein ◽  
Signal Transduction Pathway ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Transduction Pathway ◽  
Reporter Construct ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Juvenile Hemochromatosis

Abstract Juvenile hemochromatosis is a severe iron overload disorder resulting from mutations in the hemojuvelin (HJV) gene. To understand its pathogenesis, we developed Hjv−/− mice. Similar to human patients, Hjv−/− animals accumulate excess iron in the liver, pancreas and heart early in life. Tissue macrophages are iron-depleted. Hjv−/− mice express very low levels of hepcidin mRNA and, likely as a consequence, have elevated expression of the iron transporter ferroportin in enterocytes and macrophages. These results suggested that Hjv plays a role in regulating hepcidin expression. Two known Hjv homologs, Rgma and Rgmb, have previously been shown to act as bone morphogenetic protein (BMP) co-receptors. We hypothesized that Hjv regulates hepcidin expression through a BMP signal transduction pathway. We found that Hjv binds radiolabeled BMP, supporting the contention that it is a BMP co-receptor. Transfection of HepG2 cells with Hjv cDNA activated a BMP-responsive reporter construct and augmented its response to exogenous BMP. Both an anti-BMP neutralizing antibody and the natural BMP antagonist Noggin blocked this response, as did co-expressed dominant negative BMP receptor proteins. When cells were transfected with a construct carrying an Hjv mutation known to cause human disease, BMP reporter activation was significantly reduced in the presence and absence of exogenous BMP. Treatment with BMP stimulated hepcidin production in hepatoma cells and activated a reporter construct containing a fragment of the hepcidin promoter. To extend these results, we studied tissues from Hjv−/− mice. BMP signals are transduced through phosphorylation of Smad proteins. We found that Smads 1, 5 and 8 were hypophosphorylated in Hjv−/− liver, consistent with impaired BMP signaling. BMP treatment of wild type and Hjv−/− primary hepatocytes induced hepcidin expression, but induction was blunted in cells from Hjv−/− animals. Taken together, these data suggest that the normal hepatic function of Hjv is to serve as a BMP co-receptor, modulating a signal transduction pathway that culminates in hepcidin expression. [Note - Jodie L. Babitt is the first author of this abstract, but it will be presented by Franklin W. Huang, the second author]

Bmp signaling regulates proximal-distal differentiation of endoderm in mouse lung development

Development ◽  
1999 ◽  
Vol 126 (18) ◽  
pp. 4005-4015 ◽  
Author(s):  
M. Weaver ◽  
J.M. Yingling ◽  
N.R. Dunn ◽  
S. Bellusci ◽  
B.L. Hogan
Keyword(s):  
Cell Types ◽  
Surfactant Protein ◽  
Bmp Signaling ◽  
Dominant Negative ◽  
Clara Cell ◽  
Mouse Lung ◽  
Marker Genes ◽  
Distal Marker ◽  
Morphogenetic Protein

In the mature mouse lung, the proximal-distal (P-D) axis is delineated by two distinct epithelial subpopulations: the proximal bronchiolar epithelium and the distal respiratory epithelium. Little is known about the signaling molecules that pattern the lung along the P-D axis. One candidate is Bone Morphogenetic Protein 4 (Bmp4), which is expressed in a dynamic pattern in the epithelial cells in the tips of growing lung buds. Previous studies in which Bmp4 was overexpressed in the lung endoderm (Bellusci, S., Henderson, R., Winnier, G., Oikawa, T. and Hogan, B. L. M. (1996) Development 122, 1693–1702) suggested that this factor plays an important role in lung morphogenesis. To further investigate this question, two complementary approaches were utilized to inhibit Bmp signaling in vivo. The Bmp antagonist Xnoggin and, independently, a dominant negative Bmp receptor (dnAlk6), were overexpressed using the surfactant protein C (Sp-C) promoter/enhancer. Inhibiting Bmp signaling results in a severe reduction in distal epithelial cell types and a concurrent increase in proximal cell types, as indicated by morphology and expression of marker genes, including the proximally expressed hepatocyte nuclear factor/forkhead homologue 4 (Hfh4) and Clara cell marker CC10, and the distal marker Sp-C. In addition, electron microscopy demonstrates the presence of ciliated cells, a proximal cell type, in the most peripheral regions of the transgenic lungs. We propose a model in which Bmp4 is a component of an apical signaling center controlling P-D patterning. Endodermal cells at the periphery of the lung, which are exposed to high levels of Bmp4, maintain or adopt a distal character, while cells receiving little or no Bmp4 signal initiate a proximal differentiation program.

scholarly journals Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells.

1996 ◽  
Vol 15 (18) ◽  
pp. 4928-4939 ◽  
Author(s):  
Y. Tagaya ◽  
J. D. Burton ◽  
Y. Miyamoto ◽  
T. A. Waldmann
Keyword(s):  
Signal Transduction ◽  
Mast Cells ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Receptor Signal

scholarly journals Genetic evidence for signal transduction within the Bacillus subtilis GerA germinant receptor

2021 ◽  
Author(s):  
Jeremy D. Amon ◽  
Lior Artzi ◽  
David Z. Rudner
Keyword(s):  
Signal Transduction ◽  
Bacillus Subtilis ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Transduction Pathway ◽  
Sense And Respond ◽  
Enrichment Strategy ◽  
Functional Receptor

Bacterial spores can rapidly exit dormancy through the process of germination. This process begins with the activation of nutrient receptors embedded in the spore membrane. The prototypical germinant receptor in Bacillus subtilis responds to L-alanine and is thought to be a complex of proteins encoded by the genes in the gerA operon: gerAA , gerAB , and gerAC . The GerAB subunit has recently been shown to function as the nutrient sensor, but beyond contributing to complex stability, no additional functions have been attributed to the other two subunits. Here, we investigate the role of GerAA. We resurrect a previously characterized allele of gerA (termed gerA* ) that carries a mutation in gerAA and show it constitutively activates germination even in the presence of a wild-type copy of gerA . Using an enrichment strategy to screen for suppressors of gerA* , we identified mutations in all three gerA genes that restore a functional receptor. Characterization of two distinct gerAB suppressors revealed that one ( gerAB[E105K]) reduces the GerA complex's ability to respond to L-alanine, while another ( gerAB[F259S] ) disrupts the germinant signal downstream of L-alanine recognition. These data argue against models in which GerAA is directly or indirectly involved in germinant sensing. Rather, our data suggest that GerAA is responsible for transducing the nutrient signal sensed by GerAB. While the steps downstream of gerAA have yet to be uncovered, these results validate the use of a dominant-negative genetic approach in elucidating the gerA signal transduction pathway. Importance Endospore formers are a broad group of bacteria that can enter dormancy upon starvation and exit dormancy upon sensing the return of nutrients. How dormant spores sense and respond to these nutrients is poorly understood. Here, we identify a key step in the signal transduction pathway that is activated after spores detect the amino acid L-alanine. We present a model that provides a more complete picture of this process that is critical for allowing dormant spores to germinate and resume growth.

scholarly journals Genetic evidence for signal transduction within the Bacillus subtilis GerA germinant receptor

2021 ◽  
Author(s):  
Jeremy D. Amon ◽  
Lior Artzi ◽  
David Z. Rudner
Keyword(s):  
Signal Transduction ◽  
Bacillus Subtilis ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Bacterial Spores ◽  
Wild Type ◽  
Enrichment Strategy ◽  
Functional Receptor

Bacterial spores can rapidly exit dormancy through the process of germination. This process begins with the activation of nutrient receptors embedded in the spore membrane. The prototypical germinant receptor in Bacillus subtilis responds to L-alanine and is thought to be a complex of proteins encoded by the genes in the gerA operon: gerAA, gerAB, and gerAC. The GerAB subunit has recently been shown to function as the nutrient sensor, but beyond contributing to complex stability, no additional functions have been attributed to the other two subunits. Here, we investigate the role of GerAA. We resurrect a previously characterized allele of gerA (termed gerA*) that carries a mutation in gerAA and show it constitutively activates germination even in the presence of a wild-type copy of gerA. Using an enrichment strategy to screen for suppressors of gerA*, we identified mutations in all three gerA genes that restore a functional receptor. Characterization of two distinct gerAB suppressors revealed that one (gerAB-E105K) reduces the GerA complex's ability to respond to L-alanine, while another (gerAB-F259S) disrupts the germinant signal downstream of L-alanine recognition. These data argue against models in which GerAA is directly or indirectly involved in germinant sensing. Rather, our data suggest that GerAA is responsible for transducing the nutrient signal sensed by GerAB. While the steps downstream of gerAA have yet to be uncovered, these results validate the use of a dominant-negative genetic approach in elucidating the gerA signal transduction pathway.

Mothers against dpp encodes a conserved cytoplasmic protein required in DPP/TGF-beta responsive cells

Development ◽  
1996 ◽  
Vol 122 (7) ◽  
pp. 2099-2108 ◽  
Author(s):  
S.J. Newfeld ◽  
E.H. Chartoff ◽  
J.M. Graff ◽  
D.A. Melton ◽  
W.M. Gelbart
Keyword(s):  
Signal Transduction ◽  
Signal Transduction Pathway ◽  
Essential Element ◽  
Transduction Pathway ◽  
Tgf Beta ◽  
Hsp70 Promoter ◽  
Visceral Mesoderm ◽  
Immunohistochemical Studies ◽  
Midgut Development ◽  
In Cells

The proteins necessary for signal transduction in cells responding to ligands of the TGF-beta family are largely unknown. We have previously identified Mad (Mothers against dpp), a gene that interacts with the TGF-beta family member encoded by decapentaplegic (dpp) in Drosophila. Assay of Mad's role in the DPP-dependent events of embryonic midgut development demonstrates that Mad is required for any response of the visceral mesoderm or endoderm to DPP signals from the visceral mesoderm. Replacement of the normal DPP promoter with a heterologous (hsp70) promoter fails to restore DPP-dependent responses in Mad mutant midguts. Experiments utilizing Mad transgenes regulated by tissue-specific promoters show that MAD is required specifically in cells responding to DPP. Immunohistochemical studies localize MAD to the cytoplasm in all tissues examined. Experiments in Xenopus embryos demonstrate that Drosophila MAD can function in the signaling pathway of BMP-4, a vertebrate homolog of dpp. Based on these results, we propose that Mad is a highly conserved and essential element of the DPP signal transduction pathway.

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