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The authors characterize the phenotype of embryos lacking the function of sfl, which encodes an enzyme involved in the modification of heparan sulphate, and dally, which encodes a GPI-linked HSPG. Loss of function of either of these gene products impairs Wg signaling in the embryonic ectoderm and in the wing disc. Dally is suggested to function as a co-receptor, which functions with Dfz2 in the transduction of Wg signals.
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Biochemical evidence is presented that dally encodes a cell-surface heparan-sulfate-modified proteoglycan. The authors use double-stranded RNA interference to completely block dally function and thereby show that it is required for Dpp signaling in some imaginal tissues but is specifically required for Wg, and not Dpp, signaling in the embryonic epidermis. Dally is suggested to function as a tissue-specific regulatory component of both Wg and Dpp receptor complexes.
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Wg protein is believed to be actively transported from cell to cell in a process that requires endocytosis. This paper describes three mutant forms of Wg protein that retain some signaling activity in ventral, but not dorsal, epidermal cells. The mutant proteins accumulate only in Wg-expressing cells, suggesting that they cannot be transported. The fact that Wg transport can be uncoupled from signal transduction is consistent with the notion that different receptors are used for transport and signaling functions.
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Dierick H.A., Bejsovec A. Functional analysis of Wingless reveals a link between intercellular ligand transport and dorsal-cell-specific signaling. Development. 125:1998;4729-4738. Wg protein is believed to be actively transported from cell to cell in a process that requires endocytosis. This paper describes three mutant forms of Wg protein that retain some signaling activity in ventral, but not dorsal, epidermal cells. The mutant proteins accumulate only in Wg-expressing cells, suggesting that they cannot be transported. The fact that Wg transport can be uncoupled from signal transduction is consistent with the notion that different receptors are used for transport and signaling functions.
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A series of Drosophila embryos that lack defined genomic regions are analyzed for defects in Wg expression, signaling or intercellular transport. Wg signaling is severely impaired in embryos carrying deletions encompassing the candidate Wg receptors, Dfz2 and Fz. Surprisingly, Wg protein is still internalized and distributed to neighboring cells in these embryos, suggesting the existence of a separate transport receptor. Embryos carrying a distinct genomic deficiency show a very narrow distribution of Wg protein, raising the possibility that that this region contains a gene encoding the putative transporter.
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Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginal disc
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Lecuit T., Cohen S.M. Dpp receptor levels contribute to shaping the Dpp morphogen gradient in the Drosophila wing imaginal disc. Development. 125:1998;4901-4907. Dpp is shown to negatively regulate expression of its receptor, Tkv, such that complementary gradients of Dpp signaling and Tkv expression are established. Dpp target genes are hyperactivated when Tkv is ectopically expressed near the border of the Dpp signaling domain, suggesting that high levels of Tkv sensitize cells, enabling them to respond to subthreshold levels of ligand.
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An expression cloning approach is used to identify BAMBI, a truncated TGF-β-related receptor that blocks signal transduction downstream of activin and BMPs, and which is proposed to limit the signaling range of these morphogens during embryogenesis. Interestingly, the human ortholog of BAMBI, nma, is downregulated in metastatic melanoma cell lines, which raises the possibility that it functions as a tumor suppressor by inhibiting TGF-β signaling
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Hsieh J.C., Kodjabachian L., Rebbert M.L., Rattner A., Smallwood P.M., Samos C.H., Nusse R., Dawid I.B., Nathans J. A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature. 398:1999;431-436. A novel secreted protein, WIF-1, is identified that binds a variety of Wnt proteins with varying affinity and thereby inhibits their activity. WIF-1 is expressed in presomitic mesoderm and ectopically expressed WIF-1 disrupts muscle formation. Xwnt-8 is required for specification of muscle fate during gastrulation [42], but must be downregulated thereafter for normal somitogenesis to occur [43]. WIF-1 may contribute to this latter process.
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The secreted protein cerberus is shown to bind and inhibit the activity of Xwnt-8, BMP-4 and Xenopus nodal-related-1. Induction of head structures may require simultaneous inhibition of all three of these proteins, and cerebrus is thus an excellent candidate for the endogenous head organizer. Cerberus is proteolytically cleaved, and the processed form of this protein specifically inhibits nodal, but not BMP or Wnt signaling. Whether, or how, this processing event is regulated in vivo is not clear.
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Piccolo S., Agius E., Leyns L., Bhattacharyya S., Grunz H., Bouwmeester T., De Robertis E.M. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature. 397:1999;707-710. The secreted protein cerberus is shown to bind and inhibit the activity of Xwnt-8, BMP-4 and Xenopus nodal-related-1. Induction of head structures may require simultaneous inhibition of all three of these proteins, and cerebrus is thus an excellent candidate for the endogenous head organizer. Cerberus is proteolytically cleaved, and the processed form of this protein specifically inhibits nodal, but not BMP or Wnt signaling. Whether, or how, this processing event is regulated in vivo is not clear.
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Nature
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Piccolo, S.1
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Ashe H.L., Levine M. Local inhibition and long-range enhancement of Dpp signal transduction by sog. Nature. 398:1999;427-431. Sog had previously been characterized as a secreted protein that binds and inhibits the activity of Dpp. Paradoxically, sog mutant embryos lack a structure that is specified by peak levels of Dpp signaling. The authors show that sog inhibits Dpp signaling in cells located proximal to the source of sog but facilitates Dpp signaling in cells distal to this source. The mechanism by which a single protein can both inhibit and facilitate Dpp signaling is unknown.
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Engrailed and hedgehog make the range of Wingless asymmetric in Drosophila embryos
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Wg protein has been shown to be asymmetrically distributed on either side of Wg-transcribing cells in the embryonic epidermis. The authors show that Wg transport or stability is reduced in posterior cells of each segment and that a selective barrier to Wg movement exists at the posterior compartment boundary. This barrier is breached in Hh mutants.
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Sanson B., Alexandre C., Fascetti N., Vincent J.P. Engrailed and hedgehog make the range of Wingless asymmetric in Drosophila embryos. Cell. 98:1999;207-216. Wg protein has been shown to be asymmetrically distributed on either side of Wg-transcribing cells in the embryonic epidermis. The authors show that Wg transport or stability is reduced in posterior cells of each segment and that a selective barrier to Wg movement exists at the posterior compartment boundary. This barrier is breached in Hh mutants.
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(1999)
Cell
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Sanson, B.1
Alexandre, C.2
Fascetti, N.3
Vincent, J.P.4
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37
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0032541405
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BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development
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Ectopic expression of an inhibitor of selected members of the pro-protein convertase (PC) family of serine endoproteases phenocopies the effect of blocking BMP signaling in Xenopus embryos. Furin and PC6 are identified as the best candidate BMP-4 convertases during dorsoventral patterning of the embryo.
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Cui Y., Jean F., Thomas G., Christian J.L. BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. EMBO J. 17:1998;4735-4743. Ectopic expression of an inhibitor of selected members of the pro-protein convertase (PC) family of serine endoproteases phenocopies the effect of blocking BMP signaling in Xenopus embryos. Furin and PC6 are identified as the best candidate BMP-4 convertases during dorsoventral patterning of the embryo.
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(1998)
EMBO J
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Cui, Y.1
Jean, F.2
Thomas, G.3
Christian, J.L.4
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38
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0033545215
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Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases
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The authors use domain-swap experiments to convincingly demonstrate that the stability of mature nodal is regulated by the pro-domain portion of the precursor. Pro-domains of TGF-β family members have been proposed to function as molecular chaperones that aid in protein folding, but this is the first evidence that pro-domains may regulate the availability of bioactive, mature ligand.
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Constam D.B., Robertson E.J. Regulation of bone morphogenetic protein activity by pro domains and proprotein convertases. J Cell Biol. 144:1999;139-149. The authors use domain-swap experiments to convincingly demonstrate that the stability of mature nodal is regulated by the pro-domain portion of the precursor. Pro-domains of TGF-β family members have been proposed to function as molecular chaperones that aid in protein folding, but this is the first evidence that pro-domains may regulate the availability of bioactive, mature ligand.
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(1999)
J Cell Biol
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, pp. 139-149
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Constam, D.B.1
Robertson, E.J.2
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39
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0029844192
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Cholesterol modification of hedgehog signaling proteins in animal development
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Porter J.A., Young K.E., Beachy P.A. Cholesterol modification of hedgehog signaling proteins in animal development. Science. 274:1996;255-259.
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(1996)
Science
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Porter, J.A.1
Young, K.E.2
Beachy, P.A.3
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40
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15444359695
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Identification of a palmitic acid-modified form of human Sonic hedgehog
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Pepinsky R.B., Zeng C., Wen D., Rayhorn P., Baker D.P., Williams K.P., Bixler S.A., Ambrose C.M., Garber E.A., Miatkowski K.et al. Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem. 273:1998;14037-14045.
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(1998)
J Biol Chem
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Pepinsky, R.B.1
Zeng, C.2
Wen, D.3
Rayhorn, P.4
Baker, D.P.5
Williams, K.P.6
Bixler, S.A.7
Ambrose, C.M.8
Garber, E.A.9
Miatkowski, K.10
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41
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0033597141
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Association of sterol- And glycosylphosphatidylinositol-linked proteins with Drosophila raft lipid microdomains
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This paper shows that cholesterol-linked Hh is associated with specialized membrane microdomains, called rafts. Rafts have been proposed to function in protein trafficking, sorting and signal transduction.
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Rietveld A., Neutz S., Simons K., Eaton S. Association of sterol- and glycosylphosphatidylinositol-linked proteins with Drosophila raft lipid microdomains. J Biol Chem. 274:1999;12049-12054. This paper shows that cholesterol-linked Hh is associated with specialized membrane microdomains, called rafts. Rafts have been proposed to function in protein trafficking, sorting and signal transduction.
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(1999)
J Biol Chem
, vol.274
, pp. 12049-12054
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Rietveld, A.1
Neutz, S.2
Simons, K.3
Eaton, S.4
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42
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0029844213
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Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos
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Hoppler S., Brown J.D., Moon R.T. Expression of a dominant-negative Wnt blocks induction of MyoD in Xenopus embryos. Genes Dev. 10:1996;2805-2817.
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Hoppler, S.1
Brown, J.D.2
Moon, R.T.3
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43
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Post-transcriptional regulation of Xwnt-8 expression is required for normal myogenesis during vertebrate embryonic development
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Tian Q., Nakayama T., Dixon M.P., Christian J.L. Post-transcriptional regulation of Xwnt-8 expression is required for normal myogenesis during vertebrate embryonic development. Development. 126:1999;3371-3380.
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(1999)
Development
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Tian, Q.1
Nakayama, T.2
Dixon, M.P.3
Christian, J.L.4
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44
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0343967010
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Hedgehog creates a gradient of Dpp activity in Drosophila wing imaginal discs
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in press. These authors are the first to directly monitor Dpp activity in vivo. Antibodies that recognize the phosphorylated form of Mad are used to visualize the activated form of this cytoplasmic transducer of Dpp signaling in the Drosophila wing disc. Activated Mad levels are highest near the source of Dpp, but are unexpectedly low in Dpp-expressing cells. In the latter cells, Hh-mediated downregulation of the Dpp receptor, Tkv, is shown to attenuate Dpp-responsiveness and this is essential for normal patterning of the wing.
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Tanimoto H., Itoh S., ten Dijke P., Tabata T. Hedgehog creates a gradient of Dpp activity in Drosophila wing imaginal discs. Mol Cell. 2000;. in press. These authors are the first to directly monitor Dpp activity in vivo. Antibodies that recognize the phosphorylated form of Mad are used to visualize the activated form of this cytoplasmic transducer of Dpp signaling in the Drosophila wing disc. Activated Mad levels are highest near the source of Dpp, but are unexpectedly low in Dpp-expressing cells. In the latter cells, Hh-mediated downregulation of the Dpp receptor, Tkv, is shown to attenuate Dpp-responsiveness and this is essential for normal patterning of the wing.
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(2000)
Mol Cell
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Tanimoto, H.1
Itoh, S.2
Ten Dijke, P.3
Tabata, T.4
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45
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0033598964
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Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells
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Genetic analysis in Drosophila identifies a gene, dispatched (disp), the product of which is required for cholesterol-anchored, but not cholesterol-free, Hh to be released from producing cells. Disp encodes a novel putative multipass transmembrane protein that contains a sterol sensing domain.
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Burke R., Nellen D., Bellotto M., Hafen E., Senti K.A., Dickson B.J., Basler K. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified hedgehog from signaling cells. Cell. 99:1999;803-815. Genetic analysis in Drosophila identifies a gene, dispatched (disp), the product of which is required for cholesterol-anchored, but not cholesterol-free, Hh to be released from producing cells. Disp encodes a novel putative multipass transmembrane protein that contains a sterol sensing domain.
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(1999)
Cell
, vol.99
, pp. 803-815
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Burke, R.1
Nellen, D.2
Bellotto, M.3
Hafen, E.4
Senti, K.A.5
Dickson, B.J.6
Basler, K.7
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