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0950-199112762000MarDevelopment (Cambridge, England)DevelopmentEndodermal Nodal-related signals and mesoderm induction in Xenopus.117311831173-83In Xenopus, mesoderm induction by endoderm at the blastula stage is well documented, but the molecular nature of the endogenous inductive signals remains unknown. The carboxy-terminal fragment of Cerberus, designated Cer-S, provides a specific secreted antagonist of mesoderm-inducing Xenopus Nodal-Related (Xnr) factors. Cer-S does not inhibit signalling by other mesoderm inducers such as Activin, Derrière, Vg1 and BMP4, nor by the neural inducer Xnr3. In the present study we show that Cer-S blocks the induction of both dorsal and ventral mesoderm in animal-vegetal Nieuwkoop-type recombinants. During blastula stages Xnr1, Xnr2 and Xnr4 are expressed in a dorsal to ventral gradient in endodermal cells. Dose-response experiments using cer-S mRNA injections support the existence of an endogenous activity gradient of Xnrs. Xnr expression at blastula can be activated by the vegetal determinants VegT and Vg1 acting in synergy with dorsal (beta)-catenin. The data support a modified model for mesoderm induction in Xenopus, in which mesoderm induction is mediated by a gradient of multiple Nodal-related signals released by endoderm at the blastula stage.AgiusEEHoward Hughes Medical Institute, Department of Biological Chemistry, University of California, Los Angeles, CA 90095-1662, USA.OelgeschlägerMMWesselyOOKempCCDe RobertisE MEMengR37 HD021502HDNICHD NIH HHSUnited StatesR37 HD-21502-14HDNICHD NIH HHSUnited StatesJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.
EnglandDevelopment87017440950-19910DNA Primers0Intercellular Signaling Peptides and Proteins0Nodal Protein0Proteins0RNA, Messenger0Transforming Growth Factor beta0Xenopus Proteins0cer1 protein, XenopusIMAnimalsBase SequenceBlastocystcytologymetabolismDNA PrimersgeneticsEmbryonic InductionEndodermcytologymetabolismFemaleGene Expression Regulation, DevelopmentalIntercellular Signaling Peptides and ProteinsMesodermcytologymetabolismNodal ProteinOrganizers, EmbryonicProteinsgeneticsRNA, MessengergeneticsmetabolismRecombination, GeneticSignal TransductionTransforming Growth Factor betageneticsXenopusembryologygeneticsmetabolismXenopus Proteins2000222902000425902000222902008410ppublish10683171NIHMS43286PMC229210710.1242/dev.127.6.1173Belo JA, Bouwmeester T, Leyns L, Kertesz N, Gallo M, Follettie M, De Robertis EM. Cerberus-like is a secreted factor with neuralizing activity expressed in the anterior primitive endoderm of the mouse gastrula. Mech. Dev. 1997;68:45–57.9431803Bouwmeester T, Kim SH, Sasai Y, Lu B, De Robertis EM. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann’s organizer. Nature. 1996;382:595–601.8757128Boterenbrood EC, Nieuwkoop PD. The formation of the mesoderm in urodelean amphibians. V. Its regional induction by the endoderm. Wilhelm Roux’ Arch. Dev. Biol. 1973;173:319–332.28304800Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D. A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev. 1997;11:2359–2370.PMC3165189308964Chang C, Wilson PA, Mathews LS, Hemmati-Brivanlou A. A Xenopus type I activin receptor mediates mesodermal but not neural specification during embryogenesis. Development. 1997;124:827–837.9043064Clements D, Friday RV, Woodland HR. Mode of action of VegT in mesoderm and endoderm formation. Development. 1999;126:4903–4911.10518506Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, Robertson EJ. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development. 1994;120:1919–1928.7924997De Robertis EM, Kim SH, Leyns L, Piccolo S, Bachiller D, Agius E, Belo JA, Yamamoto A, Hainski-Brosseau A, Brizuela B, Wessely O, Lu B, Bouwmeester T. Patterning by genes expressed in Spemann’s organizer. Cold Spring Harbor Symp. Quant. Biol. 1997;62:169–175.9598349Dohrmann CE, Hemmati-Brivanlou A, Thomsen GJ, Fields A, Woolf TM, Melton DA. Expression of activin mRNA during early development in Xenopus laevis. Dev. Biol. 1993;157:474–483.8500654Ecochard V, Cayrol C, Foulquier F, Zaraisky A, Duprat AM. A novel TGF-β-like gene, fugacin, specifically expressed in the Spemann organizer of Xenopus. Dev. Biol. 1995;172:699–703.8612984Erter CE, Solnica-Krezel L, Wright CV. Zebrafish nodal-related 2 encodes an early mesendodermal inducer signaling from the extraembryonic yolk syncytial layer. Dev. Biol. 1998;204:361–372.9882476Fekany K, Yamanaka Y, Leung TC, Sirotkin HI, Topczewski J, Gates MA, Hibi M, Renucci A, Stemple D, Radbill A, Schier AF, Driever W, Hirano T, Talbot WS, Solnica-Krezel L. The zebrafish bozozok locus encodes Dharma, a homeodomain protein essential for induction of gastrula organizer and dorsoanterior embryonic structures. Development. 1999;126:1427–1438.10068636Feldman B, Gates MA, Egan ES, Dougan ST, Rennebeck G, Sirotkin HI, Schier AF, Talbot WS. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature. 1998;395:181–185.9744277Green JBA, Smith JC. Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate. Nature. 1990;347:391–394.1699129Green JBA, New HV, Smith JC. Responses of embryonic Xenopus cells to activin and FGF are separated by multiple dose thresholds and correspond to distinct axes of the mesoderm. Cell. 1992;71:731–739.1423628Gritsman K, Zhang J, Cheng S, Heckscher E, Talbot WS, Schier AF. The EGF-CFC protein one-eyed pinhead is essential for Nodal signaling. Cell. 1999;97:121–132.10199408Gurdon JB, Mitchell A, Mahony D. Direct and continuous assessment by cells of their position in a morphogen gradient. Nature. 1995;376:520–521.7637784Hansen CS, Marion CD, Steele K, George S, Smith WC. Direct neural induction and selective inhibition of mesoderm and epidermis inducers by Xnr3. Development. 1997;124:483–492.9053324Harland R, Gerhart J. Formation and function of Spemann’s organizer. Ann. Rev. Cell. Dev. Biol. 1997;13:611–667.9442883Heasman J. Patterning the Xenopus blastula. Development. 1997;124:4179–4191.9334267Heasman J, Crawford A, Goldstone K, Garner-Hamrick P, Gumbiner B, McCrea P, Kintner C, Noro CY, Wylie C. Overexpression of cadherins and underexpression of β-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell. 1994;79:791–803.7528101Horb ME, Thomsen GH. A vegetally localized T-box transcription factor in Xenopus eggs specifies mesoderm and endoderm and is essential for embryonic mesoderm formation. Development. 1997;124:1689–1698.9165117Hsu DR, Economides AN, Wang X, Eimon PM, Harland RM. The Xenopus dorsalizing factor gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol. Cell. 1998;1:673–683.9660951Jones CM, Kuehn MR, Hogan BLM, Smith JC, Wright CVE. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development. 1995;121:3651–3662.8582278Jones CM, Armes N, Smith JC. Signalling by TGF-β family members: short-range effects of Xnr-2 and BMP-4 contrast with the long-range effects of activin. Curr. Biol. 1996;6:1468–1475.8939607Joseph EM, Melton DA. Xnr4: A Xenopus Nodal-related gene expressed in the Spemann organizer. Dev. Biol. 1997;184:367–372.9133442Joseph EM, Melton DA. Mutant Vg1 ligands disrupt endoderm and mesoderm formation in Xenopus embryos. Development. 1998;125:2677–2685.9636082Kessler DS, Melton DA. Vertebrate embryonic induction: mesodermal and neural patterning. Science. 1994;266:596–604.7939714Kofron M, Demel T, Xanthos J, Lohr J, Sun B, Sive H, Osada SI, Wright C, Wylie C, Heasman J. Mesoderm induction in Xenopus is a zygotic event regulated by maternal VegT via TGFβ growth factors. Development. 1999;126:5759–5770.10572051Laurent MN, Blitz IL, Hashimoto C, Rothbächer U, Cho KWY. The Xenopus homeobox gene Twin mediates Wnt induction of Goosecoid in establishment of Spemann’s organizer. Development. 1997;124:4905–4916.9428427Lemaire P, Garrett N, Gurdon JB. Expression cloning of Siamois, a Xenopus homeobox gene expressed in dorsal-vegetal cells of blastulae and able to induce a complete secondary axis. Cell. 1995;81:85–94.7720076Lustig KD, Kroll KL, Sun EE, Kirschner MW. Expression cloning of a Xenopus T-related gene (Xombi) involved in mesodermal patterning and blastopore lip formation. Development. 1996;122:4001–4012.9012520McKendry R, Hsu SC, Harland RM, Grosschedl R. LEF-1/TCF proteins mediate Wnt-inducible transcription from the Xenopus nodal-related promoter. Dev. Biol. 1997;192:420–431.9441678Meno C, Gritsman K, Ohishi S, Ohfuji Y, Heckscher E, Mochida K, Shimono A, Kondoh H, Talbot WS, Robertson EJ, Schier AF, Hamada H. Mouse Lefty2 and zebrafish Antivin are feedback inhibitors of Nodal signaling during vertebrate gastrulation. Mol. Cell. 1999;4:287–298.10518210Molenaar M, van de Wetering M, Oosterwegel M, Peterson-Maduro J, Godsave S, Korinek V, Roose J, Destrée O, Clevers H. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell. 1996;86:391–399.8756721Nieuwkoop PD. The formation of the mesoderm in Urodelean amphibians. I. Induction by the endoderm. Roux’ Arch. f. Entw. Mech. 1969;162:34–373.28304543Nieuwkoop PD. The “organization center” of the amphibian embryo: its origin, spatial organization and morphogenetic action. Adv. Morphogen. 1973;10:1–39.4581327Nieuwkoop PD, Faber J. Normal table of Xenopus laevis. Garland Publishing, Inc.; New York: 1994.Nomura M, Li E. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature. 1998;393:786–790.9655392Osada SI, Wright CVE. Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis. Development. 1999;126:3229–3240.10375512Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature. 1999;397:707–710.PMC232327310067895Rebagliati MR, Toyama R, Haffter P, Dawid IB. cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl. Acad. Sci. 1998;95:9932–9937.PMC214399707578Sampath K, Rubinstein AL, Cheng AM, Liang JO, Fekany K, Solnica-Krezel L, Korzh V, Halpern ME, Wright CVE. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature. 1998;395:185–189.9744278Sasai Y, Lu B, Steinbeisser H, Geissert D, Gont LK, De Robertis EM. Xenopus chordin: a novel dorsalizing factor activated by organizer-specific homeobox genes. Cell. 1994;79:779–790.PMC30824638001117Schneider S, Steinbeisser H, Warga RM, Hausen P. β-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech. Dev. 1996;57:191–198.8843396Slack JMW. From egg to embryo. Cambridge University Press; Cambridge, UK: 1991a.Slack JMW. The nature of the mesoderm-inducing signal in Xenopus: a transfilter induction study. Development. 1991b;113:661–669.1782872Smith JC. Mesoderm-inducing factors and mesodermal patterning. Curr. Opin. Cell Biol. 1995;7:856–861.8608016Smith JC, Slack JMW. Dorsalization and neural induction: properties of the organizer in Xenopus laevis. J. Embryol. Exp. Morphol. 1983;78:299–317.6663230Smith WC, Harland RM. Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell. 1992;70:829–840.1339313Smith WC, McKendry R, Ribisi S, Jr., Harland RM. A nodal-related gene defines a physical and functional domain within the Spemann organizer. Cell. 1995;82:37–46.7606783Song J, Oh SP, Schrewe H, Nomura M, Lei H, Okano M, Gridley T, Li E. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 1999;213:157–169.10452853Steinbeisser H, De Robertis EM, Ku M, Kessler DS, Melton DA. Xenopus axis formation: induction of goosecoid by injected Xwnt-8 and activin mRNA. Development. 1993;118:499–507.7900991Sun BI, Bush SM, Collins-Racie LA, LaVallie ER, DiBlasio-Smith EA, Wolfman NM, McCoy JM, Sive HL. derrière: a TGF-β family member required for posterior development in Xenopus. Development. 1999;126:1467–1482.10068640Thisse C, Thisse B. Antivin, a novel and divergent member of the TGFβ superfamily, negatively regulates mesoderm induction. Development. 1999;126:229–240.9847237Thomsen GH, Melton DA. Processed Vg1 protein is an axial mesoderm inducer in Xenopus. Cell. 1993;74:433–441.8348610Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell. 1998;92:797–808.9529255Watabe T, Kim S, Candia A, Rothbächer U, Hashimoto C, Inoue K, Cho KWY. Molecular mechanisms of Spemann’s organizer formation: conserved growth factor synergy between Xenopus and mouse. Genes Dev. 1995;9:3038–3050.8543150Wylie C, Kofron M, Payne C, Anderson R, Hosobuchi M, Joseph E, Heasman J. Maternal β-catenin establishes a ‘dorsal signal’ in early Xenopus embryos. Development. 1996;122:2987–2996.8898213Yasuo H, Lemaire P. A two-step model for the fate determination of presumptive endodermal blastomeres in Xenopus embryos. Curr. Biol. 1999;9:869–879.10469589Zhang J, Houston DW, King ML, Payne C, Wylie C, Heasman J. The role of maternal VegT in establishing the primary germ layers in Xenopus embryos. Cell. 1998;94:515–524.9727494Zhou X, Sasaki H, Lowe L, Hogan BLM, Kuehn MR. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature. 1993;361:543–547.8429908