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Eddy M. De Robertis - One of the best experts on this subject based on the ideXlab platform.
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Bighead is a Wnt antagonist secreted by the Xenopus Spemann Organizer that promotes Lrp6 endocytosis
Proceedings of the National Academy of Sciences, 2018Co-Authors: Yi Ding, Gabriele Colozza, Eric A. Sosa, Yuki Moriyama, Samantha Rundle, Lukasz Salwinski, Eddy M. De RobertisAbstract:The Xenopus laevis embryo has been subjected to almost saturating screens for molecules specifically expressed in dorsal Spemann Organizer tissue. In this study, we performed high-throughput RNA sequencing of ectodermal explants, called animal caps, which normally give rise to epidermis. We analyzed dissociated animal cap cells that, through sustained activation of MAPK, differentiate into neural tissue. We also microinjected mRNAs for Cerberus, Chordin, FGF8, BMP4, Wnt8, and Xnr2, which induce neural or other germ layer differentiations. The searchable database provided here represents a valuable resource for the early vertebrate cell differentiation. These analyses resulted in the identification of a gene present in frog and fish, which we call Bighead. Surprisingly, at gastrula, it was expressed in the Spemann Organizer and endoderm, rather than in ectoderm as we expected. Despite the plethora of genes already mined from Spemann Organizer tissue, Bighead encodes a secreted protein that proved to be a potent inhibitor of Wnt signaling in a number of embryological and cultured cell signaling assays. Overexpression of Bighead resulted in large head structures very similar to those of the well-known Wnt antagonists Dkk1 and Frzb-1. Knockdown of Bighead with specific antisense morpholinos resulted in embryos with reduced head structures, due to increased Wnt signaling. Bighead protein bound specifically to the Wnt coreceptor lipoprotein receptor-related protein 6 (Lrp6), leading to its removal from the cell surface. Bighead joins two other Wnt antagonists, Dkk1 and Angptl4, which function as Lrp6 endocytosis regulators. These results suggest that endocytosis plays a crucial role in Wnt signaling.
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Embryonic regeneration by relocalization of the Spemann Organizer during twinning in Xenopus
Proceedings of the National Academy of Sciences, 2018Co-Authors: Yuki Moriyama, Eddy M. De RobertisAbstract:The formation of identical twins from a single egg has fascinated developmental biologists for a very long time. Previous work had shown that Xenopus blastulae bisected along the dorsal-ventral (D-V) midline (i.e., the sagittal plane) could generate twins but at very low frequencies. Here, we have improved this method by using an eyelash knife and changing saline solutions, reaching frequencies of twinning of 50% or more. This allowed mechanistic analysis of the twinning process. We unexpectedly observed that the epidermis of the resulting twins was asymmetrically pigmented at the tailbud stage of regenerating tadpoles. This pigment was entirely of maternal (oocyte) origin. Bisecting the embryo generated a large wound, which closed from all directions within 60 minutes, bringing cells normally fated to become Spemann Organizer in direct contact with predicted ventral-most cells. Lineage-tracing analyses at the four-cell stage showed that in regenerating embryos midline tissues originated from the dorsal half, while the epidermis was entirely of ventral origin. Labeling of D-V segments at the 16-cell stage showed that the more pigmented epidermis originated from the ventral-most cells, while the less-pigmented epidermis arose from the adjoining ventral segment. This suggested a displacement of the Organizer by 90°. Studies with the marker Chordin and phospho-Smad1/5/8 showed that in half embryos a new D-V gradient is intercalated at the site of the missing half. The displacement of self-organizing morphogen gradients uncovered here may help us understand not only twin formation in amphibians, but also rare cases of polyembryony.
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Depletion of Bmp2, Bmp4, Bmp7 and Spemann Organizer signals induces massive brain formation in Xenopus embryos - eScholarship
2005Co-Authors: Bruno Reversade, Hiroki Kuroda, Hojoon Lee, Ashley Mays, Eddy M. De RobertisAbstract:To address the patterning function of the Bmp2, Bmp4 and Bmp7 growth factors, we designed antisense morpholino oligomers (MO) that block their activity in Xenopus laevis. Bmp4 knockdown was sufficient to rescue the ventralizing effects caused by loss of Chordin activity. Double Bmp4 and Bmp7 knockdown inhibited tail development. Triple Bmp2/Bmp4/Bmp7 depletion further compromised trunk development but did not eliminate dorsoventral patterning. Unexpectedly, we found that blocking Spemann Organizer formation by UV treatment or beta-Catenin depletion caused BMP inhibition to have much more potent effects, abolishing all ventral development and resulting in embryos having radial central nervous system (CNS) structures. Surprisingly, dorsal signaling molecules such as Chordin, Noggin, Xnr6 and Cerberus were not re-expressed in these embryos. We conclude that BMP inhibition is sufficient for neural induction in vivo, and that in the absence of ventral BMPs, Spemann Organizer signals are not required for brain formation.
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Depletion of Bmp2, Bmp4, Bmp7 and Spemann Organizer signals induces massive brain formation in Xenopus embryos
Development, 2005Co-Authors: Bruno Reversade, Hiroki Kuroda, Hojoon Lee, Ashley Mays, Eddy M. De RobertisAbstract:To address the patterning function of the Bmp2, Bmp4 and Bmp7 growth factors, we designed antisense morpholino oligomers (MO) that block their activity in Xenopus laevis. Bmp4 knockdown was sufficient to rescue the ventralizing effects caused by loss of Chordin activity. Double Bmp4 and Bmp7 knockdown inhibited tail development. Triple Bmp2/Bmp4/Bmp7 depletion further compromised trunk development but did not eliminate dorsoventral patterning. Unexpectedly, we found that blocking Spemann Organizer formation by UV treatment or beta-Catenin depletion caused BMP inhibition to have much more potent effects, abolishing all ventral development and resulting in embryos having radial central nervous system (CNS) structures. Surprisingly, dorsal signaling molecules such as Chordin, Noggin, Xnr6 and Cerberus were not re-expressed in these embryos. We conclude that BMP inhibition is sufficient for neural induction in vivo, and that in the absence of ventral BMPs, Spemann Organizer signals are not required for brain formation.
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Analysis of Spemann Organizer formation in Xenopus embryos by cDNA macroarrays
Developmental Biology, 2004Co-Authors: Oliver Wessely, James I. Kim, Douglas Geissert, Uyen Tran, Eddy M. De RobertisAbstract:The understanding of vertebrate development has greatly benefited from the study of gastrulation in the Xenopus embryo. Over the years, the molecular dissection of the Spemann Organizer has proven to be a very fruitful source for gene discovery. Here, we report a comprehensive screen of gene expression in the Xenopus gastrula using cDNA macroarrays. Nylon filters containing more than 72,000 cDNAs from a gastrula stage library were hybridized with differential probes from embryos in which Organizer induction had been inhibited by reducing Nodal-related or maternal β-Catenin signaling. Combining the changes in gene expression levels caused by these two major signaling pathways in a single graph identified both known and novel dorsoventral regulated genes. The most highly enriched Organizer-specific genes were the secreted molecules chordin and Xnr-3, followed by the transmembrane protein paraxial protocadherin (PAPC). Ventral-specific abundant cDNAs included S10-40-H5, members of the Hyaluronan synthase family, Xvent-2 and XFD2/FoxI1. A differential probe of dorsal and ventral lips identified many more Organizer-specific cDNAs than the screens inhibiting Nodal-related and β-Catenin signaling, suggesting that additional, as yet uncharacterized signaling pathways, contribute to Organizer formation. Finally, extension of this approach to the blastula preOrganizer signaling center identified the transcription factor pintallavis/FoxA2 as a new preOrganizer component.
Richard M. Harland - One of the best experts on this subject based on the ideXlab platform.
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follistatin and noggin are excluded from the zebrafish Organizer
Developmental Biology, 1998Co-Authors: Hermann Bauer, Richard M. Harland, Aris N. Economides, Andrea Meier, Marc Hild, Scott E Stachel, Dennis J Hazelett, Matthias HammerschmidtAbstract:Abstract The patterning activity of the Spemann Organizer in early amphibian embryos has been characterized by a number of Organizer-specific secreted proteins including Chordin, Noggin, and Follistatin, which all share the same inductive properties. They can neuralize ectoderm and dorsalize ventral mesoderm by blocking the ventralizing signals Bmp2 and Bmp4. In the zebrafish, null mutations in thechordingene, namedchordino, lead to a severe reduction of Organizer activity, indicating that Chordino is an essential, but not the only, inductive signal generated by the zebrafish Organizer. A second gene required for zebrafish Organizer function ismercedes, but the molecular nature of its product is not known as yet. To investigate whether and how Follistatin and Noggin are involved in dorsoventral (D-V) patterning of the zebrafish embryo, we have now isolated and characterized their zebrafish homologues. Overexpression studies demonstrate that both proteins have the same dorsalizing properties as theirXenopushomologues. However, unlike theXenopusgenes, zebrafishfollistatinandnogginare not expressed in the Organizer region, nor are they linked to themercedesmutation. Expression of both genes starts at midgastrula stages. While no patternednogginexpression was detectable byin situhybridization during gastrulation stages, later expression is confined to presumptive cartilage cells in the branchial arches and the neurocranium and to proximal regions of the pectoral fin buds.follistatintranscripts in gastrulating embryos are confined to anterior paraxial regions, which give rise to head mesoderm and the first five somites. The dorsolateral extent of this expression domain is regulated by Bmp2b, Chordino, and Follistatin itself. In addition, transient expression was observed in a subset of cells in the posterior notochord anlage. Later,follistatinis expressed in brain, eyes, and somites. Comparison of the spatiotemporal expression pattern offollistatinandnogginwith those ofbmp2bandbmp4and overexpression studies suggest that Noggin and Follistatin may function as Bmp antagonists in later processes of zebrafish development, including late phases of D-V patterning, to refine the early pattern set up by the interaction of Chordino and Bmp2/4. It thus appears that many, but not all, aspects of early dorsoventral patterning are shared among different vertebrate species.
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The Spemann Organizer signal noggin binds and inactivates bone morphogenetic protein 4
Cell, 1996Co-Authors: Lyle B Zimmerman, José M. De Jesús-escobar, Richard M. HarlandAbstract:Signals released by the Spemann Organizer of the amphibian gastrula can directly induce neural tissue from ectoderm and can dorsalize ventral mesoderm to form muscle. The secreted polypeptide noggin mimics these activities and is expressed at the appropriate time and place to participate in the Organizer signal. Neural induction and mesoderm dorsalization are antagonized by bone morphogenetic proteins (BMPs), which induce epidermis and ventral mesoderm instead. Here we report that noggin protein binds BMP4 with high affinity and can abolish BMP4 activity by blocking binding to cognate cell-surface receptors. These data suggest that noggin secreted by the Organizer patterns the embryo by interrupting BMP signaling.
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A nodal-related gene defines a physical and functional domain within the Spemann Organizer.
Cell, 1995Co-Authors: William C Smith, Roslyn Mckendry, Stephen Ribisi, Richard M. HarlandAbstract:A functional screen for gene products that rescue dorsal development in ventralized Xenopus embryos has yielded Xenopus nodal-related 3 (Xnr3), a diverged member of the TGF beta superfamily. Xnr3 is specifically expressed in the Spemann Organizer and is only expressed in the epithelial layer of the Organizer immediately preceding and extending through gastrulation. Like noggin, Xnr3 can induce muscle in ventral mesoderm explants, consistent with a role in patterning the gastrula. In other ways, the activity of Xnr3 is different from noggin. Embryos receiving injections of Xnr3, particularly in the animal pole, send out tube-like extensions of tissue from the site of injection. These protrusions usually contain no axial mesoderm and only occasionally are positive for neural markers. It has previously been proposed that the epithelial layer of the Organizer initiates and coordinates the morphogenetic movements at gastrulation. The protrusions observed may reflect an activity of Xnr3 in promoting morphogenesis.
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Secreted noggin protein mimics the Spemann Organizer in dorsalizing Xenopus mesoderm
Nature, 1993Co-Authors: William C Smith, Anne K. Knecht, Richard M. HarlandAbstract:ADORSALIZING signal acts during gastrulation to change the specification of lateral mesodermal tissues from ventral (blood, mesenchyme) to more dorsal fates (muscle, heart, pronephros)1–3. This signal, from Spemann's Organizer, cannot be mimicked by the mesoderm inducers activin and fibroblast growth factor2. The gene noggin is expressed in the Organizer4, and could be the dorsalizing signal. Here we show that soluble noggin protein added to ventral marginal zones during gastrulation induces muscle, but that activin does not. Dorsal pattern can be partially rescued in ventralized embryos by injection of a plasmid that expresses noggin during gastrulation. The results suggest that the noggin product may be the dorsalizing signal from the Organizer.
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Expression cloning of noggin, a new dorsalizing factor localized to the Spemann Organizer in Xenopus embryos
Cell, 1992Co-Authors: William C Smith, Richard M. HarlandAbstract:Abstract We have cloned a cDNA encoding a novel polypeptide capable of inducing dorsal development in Xenopus embryos. RNA transcripts from this clone rescue normal development when injected into ventralized embryos and result in excessive head development at high doses. Therefore, we have named the cDNA noggin. noggin cDNA contains a single reading frame encoding a 26 kd protein with a hydrophobic aminoterminal sequence, suggesting that it is secreted. In Northern blot analysis this cDNA hybridizes to two mRNAs that are expressed both maternally and zygotically. Although noggin transcript is not localized in the oocyte and cleavage stage embryo, zygotic transcripts are initially restricted to the presumptive dorsal mesoderm and reach their highest levels at the gastrula stage in the dorsal lip of the blastopore (Spemann Organizer). In the neurula, noggin is transcribed in the notochord and prechordal mesoderm. The activity of exogenous noggin RNA in embryonic axis induction and the localized expression of endogenous noggin transcripts suggest that noggin plays a role in normal dorsal development.
Hiroki Kuroda - One of the best experts on this subject based on the ideXlab platform.
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expression of siamois and twin in the blastula chordin noggin signaling center is required for brain formation in xenopus laevis embryos
Mechanisms of Development, 2008Co-Authors: Hideyuki Ishibashi, E M De Robertis, Noriko Matsumura, Hiroshi Hanafusa, Kunihiro Matsumoto, Hiroki KurodaAbstract:The blastula Chordin- and Noggin-expressing (BCNE) center located in the dorsal animal region of the Xenopus blastula embryo contains both prospective anterior neuroectoderm and Spemann Organizer precursor cells. Here we show that, contrary to previous reports, the canonical Wnt target homeobox genes, Double knockdown of these genes using antisense morpholinos in Xenopus laevis blocked head formation, reduced the expression of the other BCNE center genes, upregulated Bmp4 expression, and nullified hyperdorsalization by lithium chloride. Moreover, gain- and loss-of-function experiments showed that Siamois and Twin expression is repressed by the vegetal transcription factor VegT. We propose that VegT expression causes maternal beta-Catenin signals to restrict Siamois and Twin expression to the BCNE region. A two-step inhibition of BMP signals by Siamois and Twin-- first by transcriptional repression of Bmp4 and then by activation of the expression of the BMP inhibitors Chordin and Noggin--in the BCNE center is required for head formation.
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Depletion of Bmp2, Bmp4, Bmp7 and Spemann Organizer signals induces massive brain formation in Xenopus embryos - eScholarship
2005Co-Authors: Bruno Reversade, Hiroki Kuroda, Hojoon Lee, Ashley Mays, Eddy M. De RobertisAbstract:To address the patterning function of the Bmp2, Bmp4 and Bmp7 growth factors, we designed antisense morpholino oligomers (MO) that block their activity in Xenopus laevis. Bmp4 knockdown was sufficient to rescue the ventralizing effects caused by loss of Chordin activity. Double Bmp4 and Bmp7 knockdown inhibited tail development. Triple Bmp2/Bmp4/Bmp7 depletion further compromised trunk development but did not eliminate dorsoventral patterning. Unexpectedly, we found that blocking Spemann Organizer formation by UV treatment or beta-Catenin depletion caused BMP inhibition to have much more potent effects, abolishing all ventral development and resulting in embryos having radial central nervous system (CNS) structures. Surprisingly, dorsal signaling molecules such as Chordin, Noggin, Xnr6 and Cerberus were not re-expressed in these embryos. We conclude that BMP inhibition is sufficient for neural induction in vivo, and that in the absence of ventral BMPs, Spemann Organizer signals are not required for brain formation.
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Depletion of Bmp2, Bmp4, Bmp7 and Spemann Organizer signals induces massive brain formation in Xenopus embryos
Development, 2005Co-Authors: Bruno Reversade, Hiroki Kuroda, Hojoon Lee, Ashley Mays, Eddy M. De RobertisAbstract:To address the patterning function of the Bmp2, Bmp4 and Bmp7 growth factors, we designed antisense morpholino oligomers (MO) that block their activity in Xenopus laevis. Bmp4 knockdown was sufficient to rescue the ventralizing effects caused by loss of Chordin activity. Double Bmp4 and Bmp7 knockdown inhibited tail development. Triple Bmp2/Bmp4/Bmp7 depletion further compromised trunk development but did not eliminate dorsoventral patterning. Unexpectedly, we found that blocking Spemann Organizer formation by UV treatment or beta-Catenin depletion caused BMP inhibition to have much more potent effects, abolishing all ventral development and resulting in embryos having radial central nervous system (CNS) structures. Surprisingly, dorsal signaling molecules such as Chordin, Noggin, Xnr6 and Cerberus were not re-expressed in these embryos. We conclude that BMP inhibition is sufficient for neural induction in vivo, and that in the absence of ventral BMPs, Spemann Organizer signals are not required for brain formation.
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dorsal ventral patterning and neural induction in xenopus embryos
Annual Review of Cell and Developmental Biology, 2004Co-Authors: Edward M. De Robertis, Hiroki KurodaAbstract:We review the current status of research in dorsal-ventral (D-V) patterning in vertebrates. Emphasis is placed on recent work on Xenopus, which provides a paradigm for vertebrate development based on a rich heritage of experimental embryology. D-V patterning starts much earlier than previously thought, under the influence of a dorsal nuclear -Catenin signal. At mid-blastula two signaling centers are present on the dorsal side: The prospective neuroectoderm expresses bone morphogenetic protein (BMP) antagonists, and the future dorsal endoderm secretes Nodal-related mesoderm-inducing factors. When dorsal mesoderm is formed at gastrula, a cocktail of growth factor antagonists is secreted by the Spemann Organizer and further patterns the embryo. A ventral gastrula signaling center opposes the actions of the dorsal Organizer, and another set of secreted antagonists is produced ventrally under the control of BMP4. The early dorsal -Catenin signal inhibits BMP expression at the transcriptional level and promotes expression of secreted BMP antagonists in the prospective central nervous system (CNS). In the absence of mesoderm, expression of Chordin and Noggin in ectoderm is required for anterior CNS formation. FGF (fibroblast growth factor) and IGF (insulin-like growth factor) signals are also potent neural inducers. Neural induction by anti-BMPs such as Chordin requires mitogen-activated protein kinase (MAPK) activation mediated by FGF and IGF. These multiple signals can be integrated at the level of Smad1. Phosphorylation by BMP receptor stimulates Smad1 transcriptional activity, whereas phosphorylation by MAPK has the opposite effect. Neural tissue is formed only at very low levels of activity of BMP-transducing Smads, which require the combination of both low BMP levels and high MAPK signals. Many of the molecular players that regulate D-V patterning via regulation of BMP signaling have been conserved between Drosophila and the vertebrates.
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Chordin Is Required for the Spemann Organizer Transplantation Phenomenon in Xenopus Embryos
Developmental Cell, 2003Co-Authors: Michael Oelgeschläger, Hiroki Kuroda, Bruno Reversade, Eddy M. De RobertisAbstract:We analyzed the Chordin requirement in Xenopus development. Targeting of both chordin Xenopus laevis pseudoalleles with morpholino antisense oligomers (Chd-MO) markedly decreased Chordin production. Embryos developed with moderately reduced dorsoanterior structures and expanded ventroposterior tissues, phenocopying the zebrafish chordino mutant. A strong requirement for Chordin in dorsal development was revealed by experimental manipulations. First, dorsalization by lithium chloride treatment was completely blocked by Chd-MO. Second, Chd-MO inhibited elongation and muscle differentiation in Activin-treated animal caps. Third, Chd-MO completely blocked the induction of the central nervous system (CNS), somites, and notochord by Organizer tissue transplanted to the ventral side of host embryos. Unexpectedly, transplantations into the dorsal side revealed a cell-autonomous requirement of Chordin for neural plate differentiation.
Douglas A. Melton - One of the best experts on this subject based on the ideXlab platform.
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Xnr4: a Xenopus nodal-related gene expressed in the Spemann Organizer.
Developmental Biology, 1997Co-Authors: Elaine M. Joseph, Douglas A. MeltonAbstract:We have isolated a novel TGF beta-like gene from Xenopus which is highly related to mouse nodal The gene, Xnr4, is expressed at the gastrula stage in the Spemann Organizer and at later stages in the notochord and neural tube. Ectopic expression of Xnr4 can induce and dorsalize mesoderm. These studies suggest that Xnr4, along with other nodal-related genes (Xnr1-3), may participate in mesodermal patterning and possibly neural development.
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Follistatin, an antagonist of activin, is expressed in the Spemann Organizer and displays direct neuralizing activity
Cell, 1994Co-Authors: Ali Hemmati-brivanlou, Olivia G. Kelly, Douglas A. MeltonAbstract:In the accompanying paper, we show that the expression of a dominant negative activin receptor can convert prospective ectoderm into neural tissue, which suggests that activin is an inhibitor of neuralization. Here we report the isolation and characterization of an activin antagonist, follistatin, that can induce neural tissue directly in vivo. Follistatin RNA is localized in the Spemann Organizer and notochord, tissues known to be potent neural inducers. We demonstrate that follistatin RNA and protein are able to block the activity of activin in embryonic explants. Furthermore, we show that follistatin RNA directly neuralizes ectodermal explants in the absence of detectable mesoderm. Thus, follistatin is present at the correct time and location to play a role in neural induction in vivo.
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processed vg1 protein is an axial mesoderm inducer in xenopus
Cell, 1993Co-Authors: Gerald H Thomsen, Douglas A. MeltonAbstract:Summary Vg1 is a TGFβ-related growth factor encoded by a maternal mRNA localized to vegetal blastomeres in Xenopus embryos. Vg1 precursor protein is abundant in vegetal cells, but the processed mature form has not been readily detected and no activity has been demonstrated for the putative Vg1 mature protein. We have engineered a BMP2-Vg1 fusion (BVg1) that promotes formation of mature Vg1 protein in vivo. Injection of BVg1 mRNA induces dorsal mesoderm in animal cap cells, and BVg1 expression in ultraviolet-ventralized embryos fully restores a normal dorsal axis. Blastomeres expressing BVg1 act as a Nieuwkoop center, the region that induces the Spemann Organizer. Our results lead us to suggest that localized posttranslational processing of Vg1 precursor protein on the future dorsal side of the embryo is a key step in generating dorsal mesoderm and the body axis in Xenopus.
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injected wnt rna induces a complete body axis in xenopus embryos
Cell, 1991Co-Authors: Sergei Y. Sokol, Jan L. Christian, Randall T. Moon, Douglas A. MeltonAbstract:Studies in Xenopus have shown that growth factors of the TGF beta and Wnt oncogene families can mimic aspects of dorsal axis formation. Here we directly compare the inductive properties of two Wnt proteins by injecting synthetic mRNA into developing embryos. The results show that Wnt-1 and Xwnt-8 can induce a new and complete dorsal axis and can rescue the development of axis-deficient, UV-irradiated embryos. In contrast, activin mRNA injection induces only a partial dorsal axis that lacks anterior structures. These studies demonstrate that the mechanism of Wnt-induced axis duplication results from the creation of an independent Spemann Organizer. The relationship between the properties of the endogenous dorsal inducer and the effects of Wnts and activins is discussed.
Robert A Weinberg - One of the best experts on this subject based on the ideXlab platform.
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the Spemann Organizer gene goosecoid promotes tumor metastasis
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Kimberly A Hartwell, Beth Muir, Ferenc Reinhardt, Anne E Carpenter, Dennis C Sgroi, Robert A WeinbergAbstract:The process of invasion and metastasis during tumor progression is often reminiscent of cell migration events occurring during embryonic development. We hypothesized that genes controlling cellular changes in the Spemann Organizer at gastrulation might be reactivated in tumors. The Goosecoid homeobox transcription factor is a known executer of cell migration from the Spemann Organizer. We found that indeed Goosecoid is overexpressed in a majority of human breast tumors. Ectopic expression of Goosecoid in human breast cells generated invasion-associated cellular changes, including an epithelial–mesenchymal transition. TGF-β signaling, known to promote metastasis, induced Goosecoid expression in human breast cells. Moreover, Goosecoid significantly enhanced the ability of breast cancer cells to form pulmonary metastases in mice. These results demonstrate that Goosecoid promotes tumor cell malignancy and suggest that other conserved Organizer genes may function similarly in human cancer.
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The Spemann Organizer gene, Goosecoid, promotes tumor metastasis
Proceedings of the National Academy of Sciences, 2006Co-Authors: Kimberly A Hartwell, Beth Muir, Ferenc Reinhardt, Anne E Carpenter, Dennis C Sgroi, Robert A WeinbergAbstract:The process of invasion and metastasis during tumor progression is often reminiscent of cell migration events occurring during embryonic development. We hypothesized that genes controlling cellular changes in the Spemann Organizer at gastrulation might be reactivated in tumors. The Goosecoid homeobox transcription factor is a known executer of cell migration from the Spemann Organizer. We found that indeed Goosecoid is overexpressed in a majority of human breast tumors. Ectopic expression of Goosecoid in human breast cells generated invasion-associated cellular changes, including an epithelial–mesenchymal transition. TGF-β signaling, known to promote metastasis, induced Goosecoid expression in human breast cells. Moreover, Goosecoid significantly enhanced the ability of breast cancer cells to form pulmonary metastases in mice. These results demonstrate that Goosecoid promotes tumor cell malignancy and suggest that other conserved Organizer genes may function similarly in human cancer.