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• W2077052512 abstract "Transforming growth factor-β superfamily members play important roles in the early development of animals. Activin and the Xenopus nodal related proteins 1, 2, and 4 induce muscle actin from Xenopus ectodermal explants, whereas the bone morphogenetic proteins 4 and 7 induce ectoderm to differentiate as epidermis. Bone morphogenetic proteins are antagonized by soluble binding proteins such as noggin and chordin, which leads to expression of neural cell adhesion molecule in animal caps. The transforming growth factor-β superfamily member Xenopusnodal-related 3 also induces the neural cell adhesion molecule through inhibition of bone morphogenetic proteins. Therefore, whereasXenopus nodal-related 2 and 3 share a high amount of sequence homology, they lead to very different cell fates. This study investigates the functional domains that distinguish the activities of these two factors. It was found that mutually exclusive regions of nodal-related 2 and 3 were required for activity. The central region of the mature domain is required for nodal-related 2 to induce muscle actin, whereas the N- and C-terminal ends of the mature domain are required for nodal-related 3 to induce neural cell adhesion molecule. These results help to define the minimal domains required for the unique activities of these factors. Transforming growth factor-β superfamily members play important roles in the early development of animals. Activin and the Xenopus nodal related proteins 1, 2, and 4 induce muscle actin from Xenopus ectodermal explants, whereas the bone morphogenetic proteins 4 and 7 induce ectoderm to differentiate as epidermis. Bone morphogenetic proteins are antagonized by soluble binding proteins such as noggin and chordin, which leads to expression of neural cell adhesion molecule in animal caps. The transforming growth factor-β superfamily member Xenopusnodal-related 3 also induces the neural cell adhesion molecule through inhibition of bone morphogenetic proteins. Therefore, whereasXenopus nodal-related 2 and 3 share a high amount of sequence homology, they lead to very different cell fates. This study investigates the functional domains that distinguish the activities of these two factors. It was found that mutually exclusive regions of nodal-related 2 and 3 were required for activity. The central region of the mature domain is required for nodal-related 2 to induce muscle actin, whereas the N- and C-terminal ends of the mature domain are required for nodal-related 3 to induce neural cell adhesion molecule. These results help to define the minimal domains required for the unique activities of these factors. transforming growth factor-β bone morphogenetic protein Xenopus nodal-related muscle actin neural cell adhesion molecule Tris-buffered saline TBS with 3% dried milk and 0.1% Tween The transforming growth factor-β (TGF-β)1 superfamily is composed of a myriad of related secreted proteins that are important regulators of development and physiology in both vertebrates and invertebrates (1.Heldin C.-H. Miyazono K. ten Dijke P. Nature. 1997; 390: 465-471Crossref PubMed Scopus (3314) Google Scholar). Most TGF-βs are synthesized as proproteins that are biologically inactive until proteolytically processed at R-X-(K/R)-R and R-X-X-R consensus sequences by subtilisin-like proprotein convertases (2.Creemers J.W. Kormelink P.J. Roebroek A.J. Nakayama K. Van de Ven W.J. FEBS Lett. 1993; 336: 65-69Crossref PubMed Scopus (40) Google Scholar, 3.Hosaka M. Murakami K. Nakayama K. Biomed. Res. 1994; 16: 383-390Crossref Scopus (24) Google Scholar, 4.Molloy S.S. Bresnahan P.A. Leppla S.H. Klimpel K.R. Thomas G. J. Biol. Chem. 1992; 267: 16396-16402Abstract Full Text PDF PubMed Google Scholar). Active TGF-β proteins consist of two 12–16-kDa peptides that show varying ability to function as homo- and heterodimers. Superfamily members have seven highly conserved cysteines in the C-terminal mature domain that form intra- and interchain disulfide bonds. Within the monomer, disulfide bond pairs are formed between the first and fifth, second and sixth, and third and seventh cysteines. The fourth conserved cysteine makes an interchain bond between dimer subunits. Another conserved feature of the superfamily is a glycine residue between the second and third cysteines, within the consensus sequence CXGXC. It is thought that steric hindrance would require a glycine (Fig. 1, indicated by an asterisk) in this position for proper folding, because two disulfide bonds form a closed ring on either side of this residue, which prevents its substitution (5.Griffith D.L. Keck P.C. Sampath T.K. Rueger D.C. Carlson W.D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 878-883Crossref PubMed Scopus (245) Google Scholar, 6.Schlunegger M.P. Grutter M.G. Nature. 1992; 358: 430-434Crossref PubMed Scopus (284) Google Scholar).Three-dimensional structural studies of TGF-βs 1, 2, and 3, as well as bone morphogenetic proteins (BMPs) 2 and 7 predict a conserved “cysteine knot” structure that has been described as a “left hand” (Fig. 1) (5.Griffith D.L. Keck P.C. Sampath T.K. Rueger D.C. Carlson W.D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 878-883Crossref PubMed Scopus (245) Google Scholar, 6.Schlunegger M.P. Grutter M.G. Nature. 1992; 358: 430-434Crossref PubMed Scopus (284) Google Scholar, 7.Daopin S. Li M. Davies D.R. Proteins Struct. Funct. Genet. 1993; 17: 176-192Crossref PubMed Scopus (45) Google Scholar, 8.Hinck A.P. Archer S.J. Qian S.W. Roberts A.B. Sporn M.B. Weatherbee J.A. Tsang R. Lucas M.L.-S. Zhang B.-L. Wenker J. Torchia D.A. Biochemistry. 1996; 35: 8517-8534Crossref PubMed Scopus (148) Google Scholar, 9.Mittl P.R. Priestle J.P. Cox D.A. McMaster G. Cerletti N. Grutter M.G. Protein Sci. 1996; 5: 1261-1271Crossref PubMed Scopus (127) Google Scholar, 10.Scheufler C. Sebald W. Hulsmeyer M. J. Mol. Biol. 1999; 287: 103-115Crossref PubMed Scopus (292) Google Scholar). The “heel” of the hand structure is an α-helix formed by the amino acids between the third and fourth cysteines. Extending out from this are two long loops consisting of β-sheets that form “fingers.” The N-terminal amino acid region of the mature domain extending from the cleavage site to the first conserved cysteine represents the “thumb” (also referred to as the proknot sequence, (10.Scheufler C. Sebald W. Hulsmeyer M. J. Mol. Biol. 1999; 287: 103-115Crossref PubMed Scopus (292) Google Scholar)). Members of the TGF-β subfamily (TGF-βs 1–5) and activin have two additional conserved cysteines in this region, which form a disulfide bond anchoring a short α-helix to the first β-sheet of finger 1. Because most other superfamily members share only the seven conserved cysteines, they lack this additional disulfide bond. In BMP2 and BMP7, the thumb region is disordered and cannot be resolved in electron density maps, so the structure of this region in these superfamily members is unknown.Members of the nodal subfamily of the TGF-βs play important roles in vertebrate mesoderm induction and patterning (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 12.Toyama R. O'Connell M.L. Wright C.V.E. Kuehn M.R. Dawid I.B. Development. 1995; 121: 383-391Crossref PubMed Google Scholar, 13.Zhou X. Sasaki H. Lowe L. Hogan B.L. Kuehn M.R. Nature. 1993; 361: 543-547Crossref PubMed Scopus (515) Google Scholar). Whereas the mouse and chick appear to have single members of the nodal gene family, duplications have led to at least four family members inXenopus (Xnr1–4) and two in zebrafish (squintand cyclops) (14.Feldman B. Gates M.A. Egan E.S. Dougan S.T. Rennebeck G. Sirotkin H.I. Schier A.F. Talbot W.S. Nature. 1998; 395: 181-185Crossref PubMed Scopus (548) Google Scholar, 15.Rebagliati M.R. Toyama R. Haffter P. Dawid I.B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9932-9937Crossref PubMed Scopus (328) Google Scholar, 16.Sampath K. Rubinstein A.L. Cheng A.M.S. Liang J.O. Fekany K. Solnica-Krezel L. Korzh V. Halpern M.E. Wright C.V. Nature. 1998; 395: 185-189Crossref PubMed Scopus (408) Google Scholar). Comparison of predicted amino acid sequences indicates that Xnr1, Xnr2, and Xnr3 are more closely related to each other than to Xnr4. Most notably, Xnr1, Xnr2, and Xnr3 share the unique feature of having the sequence CXXC between the fourth and fifth conserved cysteines. This sequence is also found in chick nodal and zebrafish squint. Xnr4, mouse nodal, and zebrafish cyclops, as well as the majority of other TGF-β superfamily members, have the sequence CC for these two cysteines. Xenopusnodal-related 3 (Xnr3) is unique among the nodal subfamily in having several primary structure features that diverge from the TGF-β superfamily consensus (17.Smith W.C. McKendry R.M. Ribisi S. Harland R.M. Cell. 1995; 82: 37-46Abstract Full Text PDF PubMed Scopus (281) Google Scholar). First, Xnr3 is missing the last of the seven conserved cysteines. Second, whereas all other superfamily members have a glycine located between the second and third cysteines, Xnr3 has a serine in this position. Perhaps this substitution is allowed because Xnr3 lacks one of the two disulfide bonds that constrains this residue to a glycine in other superfamily members. Together these observations suggest that Xnr3 does not form the characteristic knot structure (Fig.1).Xnr3 also has biological activity in developing Xenopusembryos that differ markedly from the other nodal-related factors. InXenopus animal cap induction assays, Xnr1, 2, and 4 induce the mesodermal markers brachyury (when assayed at early gastrula stage) and muscle actin (MA) at tailbud stage (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 18.Joseph E.M. Melton D.A. Dev. Biol. 1997; 184: 367-372Crossref PubMed Scopus (135) Google Scholar). All three also have the ability to rescue mesoderm in VegT-depleted embryos (19.Kofron M. Demel T. Xanthos J. Lohr J. Sun B. Sive H. Osada S. Wright C. Wylie C. Heasman J. Development. 1999; 126: 5759-5770Crossref PubMed Google Scholar). The related factors in the mouse and zebrafish (nodal, squint, and cyclops) induce mesodermal markers in the Xenopus assay (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 16.Sampath K. Rubinstein A.L. Cheng A.M.S. Liang J.O. Fekany K. Solnica-Krezel L. Korzh V. Halpern M.E. Wright C.V. Nature. 1998; 395: 185-189Crossref PubMed Scopus (408) Google Scholar, 20.Erter C.E. Solnica-Krezel L. Wright C.V. Dev. Biol. 1998; 204: 361-372Crossref PubMed Scopus (150) Google Scholar). However, Xnr3 blocks the activities of the TGF-β family members BMP4 and activin, does not induce brachyury or MA, and instead induces the neural cell adhesion molecule (NCAM). Based on these and other findings, we have speculated that Xnr3 may function as a BMP4 and activin receptor antagonist (21.Hansen C.S. Marion C.D. Steele K. George S. Smith W.C. Development. 1997; 124: 483-492Crossref PubMed Google Scholar). Although there are several possible mechanisms by which Xnr3 could inhibit these TGF-β superfamily members, observations that Xnr3 can inhibit soluble activin protein excludes a mechanism by which dysfunctional dimers were formed. Also, the fact that Xnr3 does not inhibit a constitutively active receptor supports the receptor antagonist model (21.Hansen C.S. Marion C.D. Steele K. George S. Smith W.C. Development. 1997; 124: 483-492Crossref PubMed Google Scholar). In addition to Xnr3, several other TGF-βs have been postulated to be antagonists, including lefty, inhibin, and antivin (22.Lebrun J.J. Vale W.W. Mol. Cell. Biol. 1997; 17: 1682-1691Crossref PubMed Scopus (144) Google Scholar, 23.Meno C. Ito Y. Saijoh Y. Matsuda Y. Tashiro K. Kuhara S. Hamada H. Genes Cells. 1997; 8: 513-524Crossref Scopus (229) Google Scholar, 24.Thisse C. Thisse B. Development. 1999; 126: 229-240Crossref PubMed Google Scholar, 25.Xu J. McKeehan K. Matsuzaki K. McKeehan W.L. J. Biol. Chem. 1995; 270: 6308-6313Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). A comparison of the primary structure of these putative antagonists does not readily suggest common features to account for their activities. Thus, it is possible that the putative TGF-β receptor antagonists evolved independently and may use different strategies for binding, but not activating, receptors.The nodal-related factors in Xenopus present a unique model system for studying structural features that are responsible for divergent activities of closely related TGF-β superfamily members. Among the nodal-related genes, Xnr3 is most closely related to Xnr2. Using a Xenopus animal cap assay and Northern blotting, the NCAM-inducing activity of Xnr3 and the MA-inducing activity of Xnr2 are easily distinguished. We have used this assay to characterize a number of chimeras and mutations of these two factors to determine which regions are required for specifying their divergent activities. The results show that the regions needed for NCAM and MA induction are different and that these regions are different from those found to be important for TGF-β activity. The transforming growth factor-β (TGF-β)1 superfamily is composed of a myriad of related secreted proteins that are important regulators of development and physiology in both vertebrates and invertebrates (1.Heldin C.-H. Miyazono K. ten Dijke P. Nature. 1997; 390: 465-471Crossref PubMed Scopus (3314) Google Scholar). Most TGF-βs are synthesized as proproteins that are biologically inactive until proteolytically processed at R-X-(K/R)-R and R-X-X-R consensus sequences by subtilisin-like proprotein convertases (2.Creemers J.W. Kormelink P.J. Roebroek A.J. Nakayama K. Van de Ven W.J. FEBS Lett. 1993; 336: 65-69Crossref PubMed Scopus (40) Google Scholar, 3.Hosaka M. Murakami K. Nakayama K. Biomed. Res. 1994; 16: 383-390Crossref Scopus (24) Google Scholar, 4.Molloy S.S. Bresnahan P.A. Leppla S.H. Klimpel K.R. Thomas G. J. Biol. Chem. 1992; 267: 16396-16402Abstract Full Text PDF PubMed Google Scholar). Active TGF-β proteins consist of two 12–16-kDa peptides that show varying ability to function as homo- and heterodimers. Superfamily members have seven highly conserved cysteines in the C-terminal mature domain that form intra- and interchain disulfide bonds. Within the monomer, disulfide bond pairs are formed between the first and fifth, second and sixth, and third and seventh cysteines. The fourth conserved cysteine makes an interchain bond between dimer subunits. Another conserved feature of the superfamily is a glycine residue between the second and third cysteines, within the consensus sequence CXGXC. It is thought that steric hindrance would require a glycine (Fig. 1, indicated by an asterisk) in this position for proper folding, because two disulfide bonds form a closed ring on either side of this residue, which prevents its substitution (5.Griffith D.L. Keck P.C. Sampath T.K. Rueger D.C. Carlson W.D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 878-883Crossref PubMed Scopus (245) Google Scholar, 6.Schlunegger M.P. Grutter M.G. Nature. 1992; 358: 430-434Crossref PubMed Scopus (284) Google Scholar). Three-dimensional structural studies of TGF-βs 1, 2, and 3, as well as bone morphogenetic proteins (BMPs) 2 and 7 predict a conserved “cysteine knot” structure that has been described as a “left hand” (Fig. 1) (5.Griffith D.L. Keck P.C. Sampath T.K. Rueger D.C. Carlson W.D. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 878-883Crossref PubMed Scopus (245) Google Scholar, 6.Schlunegger M.P. Grutter M.G. Nature. 1992; 358: 430-434Crossref PubMed Scopus (284) Google Scholar, 7.Daopin S. Li M. Davies D.R. Proteins Struct. Funct. Genet. 1993; 17: 176-192Crossref PubMed Scopus (45) Google Scholar, 8.Hinck A.P. Archer S.J. Qian S.W. Roberts A.B. Sporn M.B. Weatherbee J.A. Tsang R. Lucas M.L.-S. Zhang B.-L. Wenker J. Torchia D.A. Biochemistry. 1996; 35: 8517-8534Crossref PubMed Scopus (148) Google Scholar, 9.Mittl P.R. Priestle J.P. Cox D.A. McMaster G. Cerletti N. Grutter M.G. Protein Sci. 1996; 5: 1261-1271Crossref PubMed Scopus (127) Google Scholar, 10.Scheufler C. Sebald W. Hulsmeyer M. J. Mol. Biol. 1999; 287: 103-115Crossref PubMed Scopus (292) Google Scholar). The “heel” of the hand structure is an α-helix formed by the amino acids between the third and fourth cysteines. Extending out from this are two long loops consisting of β-sheets that form “fingers.” The N-terminal amino acid region of the mature domain extending from the cleavage site to the first conserved cysteine represents the “thumb” (also referred to as the proknot sequence, (10.Scheufler C. Sebald W. Hulsmeyer M. J. Mol. Biol. 1999; 287: 103-115Crossref PubMed Scopus (292) Google Scholar)). Members of the TGF-β subfamily (TGF-βs 1–5) and activin have two additional conserved cysteines in this region, which form a disulfide bond anchoring a short α-helix to the first β-sheet of finger 1. Because most other superfamily members share only the seven conserved cysteines, they lack this additional disulfide bond. In BMP2 and BMP7, the thumb region is disordered and cannot be resolved in electron density maps, so the structure of this region in these superfamily members is unknown. Members of the nodal subfamily of the TGF-βs play important roles in vertebrate mesoderm induction and patterning (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 12.Toyama R. O'Connell M.L. Wright C.V.E. Kuehn M.R. Dawid I.B. Development. 1995; 121: 383-391Crossref PubMed Google Scholar, 13.Zhou X. Sasaki H. Lowe L. Hogan B.L. Kuehn M.R. Nature. 1993; 361: 543-547Crossref PubMed Scopus (515) Google Scholar). Whereas the mouse and chick appear to have single members of the nodal gene family, duplications have led to at least four family members inXenopus (Xnr1–4) and two in zebrafish (squintand cyclops) (14.Feldman B. Gates M.A. Egan E.S. Dougan S.T. Rennebeck G. Sirotkin H.I. Schier A.F. Talbot W.S. Nature. 1998; 395: 181-185Crossref PubMed Scopus (548) Google Scholar, 15.Rebagliati M.R. Toyama R. Haffter P. Dawid I.B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9932-9937Crossref PubMed Scopus (328) Google Scholar, 16.Sampath K. Rubinstein A.L. Cheng A.M.S. Liang J.O. Fekany K. Solnica-Krezel L. Korzh V. Halpern M.E. Wright C.V. Nature. 1998; 395: 185-189Crossref PubMed Scopus (408) Google Scholar). Comparison of predicted amino acid sequences indicates that Xnr1, Xnr2, and Xnr3 are more closely related to each other than to Xnr4. Most notably, Xnr1, Xnr2, and Xnr3 share the unique feature of having the sequence CXXC between the fourth and fifth conserved cysteines. This sequence is also found in chick nodal and zebrafish squint. Xnr4, mouse nodal, and zebrafish cyclops, as well as the majority of other TGF-β superfamily members, have the sequence CC for these two cysteines. Xenopusnodal-related 3 (Xnr3) is unique among the nodal subfamily in having several primary structure features that diverge from the TGF-β superfamily consensus (17.Smith W.C. McKendry R.M. Ribisi S. Harland R.M. Cell. 1995; 82: 37-46Abstract Full Text PDF PubMed Scopus (281) Google Scholar). First, Xnr3 is missing the last of the seven conserved cysteines. Second, whereas all other superfamily members have a glycine located between the second and third cysteines, Xnr3 has a serine in this position. Perhaps this substitution is allowed because Xnr3 lacks one of the two disulfide bonds that constrains this residue to a glycine in other superfamily members. Together these observations suggest that Xnr3 does not form the characteristic knot structure (Fig.1). Xnr3 also has biological activity in developing Xenopusembryos that differ markedly from the other nodal-related factors. InXenopus animal cap induction assays, Xnr1, 2, and 4 induce the mesodermal markers brachyury (when assayed at early gastrula stage) and muscle actin (MA) at tailbud stage (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 18.Joseph E.M. Melton D.A. Dev. Biol. 1997; 184: 367-372Crossref PubMed Scopus (135) Google Scholar). All three also have the ability to rescue mesoderm in VegT-depleted embryos (19.Kofron M. Demel T. Xanthos J. Lohr J. Sun B. Sive H. Osada S. Wright C. Wylie C. Heasman J. Development. 1999; 126: 5759-5770Crossref PubMed Google Scholar). The related factors in the mouse and zebrafish (nodal, squint, and cyclops) induce mesodermal markers in the Xenopus assay (11.Jones M. Hogan B.L.M. Kuehn M.R. Smith J.C. Wright C.V.E. Development. 1995; 121: 3651-3662Crossref PubMed Google Scholar, 16.Sampath K. Rubinstein A.L. Cheng A.M.S. Liang J.O. Fekany K. Solnica-Krezel L. Korzh V. Halpern M.E. Wright C.V. Nature. 1998; 395: 185-189Crossref PubMed Scopus (408) Google Scholar, 20.Erter C.E. Solnica-Krezel L. Wright C.V. Dev. Biol. 1998; 204: 361-372Crossref PubMed Scopus (150) Google Scholar). However, Xnr3 blocks the activities of the TGF-β family members BMP4 and activin, does not induce brachyury or MA, and instead induces the neural cell adhesion molecule (NCAM). Based on these and other findings, we have speculated that Xnr3 may function as a BMP4 and activin receptor antagonist (21.Hansen C.S. Marion C.D. Steele K. George S. Smith W.C. Development. 1997; 124: 483-492Crossref PubMed Google Scholar). Although there are several possible mechanisms by which Xnr3 could inhibit these TGF-β superfamily members, observations that Xnr3 can inhibit soluble activin protein excludes a mechanism by which dysfunctional dimers were formed. Also, the fact that Xnr3 does not inhibit a constitutively active receptor supports the receptor antagonist model (21.Hansen C.S. Marion C.D. Steele K. George S. Smith W.C. Development. 1997; 124: 483-492Crossref PubMed Google Scholar). In addition to Xnr3, several other TGF-βs have been postulated to be antagonists, including lefty, inhibin, and antivin (22.Lebrun J.J. Vale W.W. Mol. Cell. Biol. 1997; 17: 1682-1691Crossref PubMed Scopus (144) Google Scholar, 23.Meno C. Ito Y. Saijoh Y. Matsuda Y. Tashiro K. Kuhara S. Hamada H. Genes Cells. 1997; 8: 513-524Crossref Scopus (229) Google Scholar, 24.Thisse C. Thisse B. Development. 1999; 126: 229-240Crossref PubMed Google Scholar, 25.Xu J. McKeehan K. Matsuzaki K. McKeehan W.L. J. Biol. Chem. 1995; 270: 6308-6313Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). A comparison of the primary structure of these putative antagonists does not readily suggest common features to account for their activities. Thus, it is possible that the putative TGF-β receptor antagonists evolved independently and may use different strategies for binding, but not activating, receptors. The nodal-related factors in Xenopus present a unique model system for studying structural features that are responsible for divergent activities of closely related TGF-β superfamily members. Among the nodal-related genes, Xnr3 is most closely related to Xnr2. Using a Xenopus animal cap assay and Northern blotting, the NCAM-inducing activity of Xnr3 and the MA-inducing activity of Xnr2 are easily distinguished. We have used this assay to characterize a number of chimeras and mutations of these two factors to determine which regions are required for specifying their divergent activities. The results show that the regions needed for NCAM and MA induction are different and that these regions are different from those found to be important for TGF-β activity. We thank Chris Wright for the gift of the Xnr2 plasmid, Shannon Davis and Lisa Belluzzi for their comments on the manuscript, and Rolf Christoffersen for expert computer assistance." @default.
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• W2077052512 title "Primary Structure Requirements for XenopusNodal-related 3 and a Comparison with Regions Required byXenopus Nodal-related 2" @default.
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