Nodal Signaling in Vertebrate Development

Annual Review of Cell and Developmental Biology

Volumn 19, Issue , 2003, Pages 589-621

  Schier, Alexander F ^a  

^a NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Endoderm; Feedback inhibition; Left right; Mesoderm; Morphogen; TGF

Indexed keywords

ACTIN; ACTIVIN RECEPTOR; SMAD2 PROTEIN; TRANSFORMING GROWTH FACTOR BETA;

AUTOREGULATION; CAENORHABDITIS ELEGANS; CELL FUNCTION; CONFERENCE PAPER; DROSOPHILA; EMBRYO DEVELOPMENT; ENDODERM; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; VERTEBRATE; XENOPUS LAEVIS;

ANIMALS; BODY PATTERNING; EMBRYO; FEEDBACK, BIOCHEMICAL; FUNCTIONAL LATERALITY; HUMANS; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA; VERTEBRATES;

CAENORHABDITIS; CAENORHABDITIS ELEGANS; CERBERUS; VERTEBRATA; XENOPUS LAEVIS;

EID: 0345255908     PISSN: 10810706     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.cellbio.19.041603.094522     Document Type: Conference Paper

References (146)

1. Adamson ED, Minchiotti G, Salomon DS. 2002. Cripto: a tumor growth factor and more. J. Cell. Physiol. 190:267-78
2. Agathon A, Thisse B, Thisse C. 2001. Morpholino knock-down of antivin1 and antivin2 up-regulates nodal signaling. Genesis 30:178-82
3. Agius E, Oelgeschlager M, Wessely O, Kemp C, DeRobertis EM. 2000. Endodermal Nodal-related signals and mesoderm induction in Xenopus. Development 127:1173-83
4. Altmann CR, Chang C, Munoz-Sanjuan I, Bell E, Heke M, et al. 2002. The latent-TGFbeta-binding-protein-1 (LTBP-1) is expressed in the organizer and regulates nodal and activin signaling. Dev. Biol. 248:118-27
5. Aoki TO, Mathieu J, Saint-Etienne L, Rebagliati MR, Peyrieras N, Rosa FM. 2002. Regulation of nodal signalling and mesendoderm formation by TARAM-A, a TGFbeta-related type I receptor. Dev. Biol. 241:273-88
6. Attisano L, Wrana JL. 2002. Signal transduction by the TGF-beta superfamily. Science 296:1646-47
7. Bamford RN, Roessler E, Burdine RD, Saplakoglu U, dela Cruz J, et al. 2000. Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat. Genet. 26:365-69
8. Beck S, Le Good JA, Guzman M, Ben Haim N, Roy K, et al. 2002. Extraembryonic proteases regulate Nodal signalling during gastrulation. Nat. Cell Biol. 4:981-85
9. Beddington RS, Robertson EJ. 1999. Axis development and early asymmetry in mammals. Cell 96:195-209
10. Bell E, Munoz-Sanjuan I, Altmann CR, Vonica A, Brivanlou AH. 2003. Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development 130:1381-89
11. Belo JA, Bachiller D, Agius E, Kemp C, Borges AC, et al. 2000. Cerberus-like is a secreted BMP and nodal antagonist not essential for mouse development. Genesis 26:265-70
12. Bertocchini F, Stern CD. 2002. The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling. Dev. Cell 3:735-44
13. Bianco C, Adkins HB, Wechselberger C, Seno M, Normanno N, et al. 2002. Cripto-1 activates nodal-and ALK4-dependent and -independent signaling pathways in mammary epithelial cells. Mol. Cell. Biol. 22:2586-97
14. Bisgrove BW, Essner JJ, Yost HJ. 1999. Regulation of midline development by antagonism of lefty and nodal signaling. Development 126:3253-62
15. Bouwmeester T, Kim S-H, Sasai Y, Lu B, De Robertis EM. 1996. Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer. Nature 382:595-601
16. Branford WW, Yost HJ. 2002. Lefty-dependent inhibition of nodal-and wnt-responsive organizer gene expression is essential for normal gastrulation. Curr. Biol. 12:2136-41
17. Brennan J, Lu CC, Norris DP, Rodriguez TA, Beddington RS, Robertson EJ. 2001. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411:965-69
18. Brennan J, Norris DP, Robertson EJ. 2002. Nodal activity in the node governs left-right asymmetry. Genes Dev. 16:2339-44
19. Burdine RD, Schier AF. 2000. Conserved and divergent mechanisms in left-right axis formation. Genes Dev. 14:763-76
20. Capdevila J, Vogan KJ, Tabin CJ, Belmonte JCI. 2000. Mechanisms of left-right determination in vertebrates. Cell 101:9-21
21. Carmany-Rampey A, Schier AF. 2001. Single-cell internalization during zebrafish gastrulation. Curr. Biol. 11:1261-65
22. Chang C, Eggen BJ, Weinstein DC, Brivanlou AH. 2003. Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel mechanisms. Dev. Biol. 255:1-11
23. Chen S, Kimelman D. 2000. The role of the yolk syncytial layer in germ layer patterning in zebrafish. Development 127:4681-89
24. Chen Y, Schier AF. 2001. The zebrafish Nodal signal Squint functions as a morphogen. Nature 411:607-10
25. Chen Y, Schier AF. 2002. Lefty proteins are long-range inhibitors of squint-mediated nodal signaling. Curr. Biol. 12:2124-28
26. Cheng AM, Thisse B, Thisse C, Wright CV. 2000. The lefty-related factor Xatv acts as a feedback inhibitor of nodal signaling in mesoderm induction and L-R axis development in Xenopus. Development 127:1049-61
27. Cheng SK, Olale F, Bennett JT, Brivanlou AH, Schier AF. 2003. EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1. Genes Dev. 17:31-36
28. Collignon J, Varlet I, Robertson EJ. 1996. Relationship between asymmetric nodal expression and the direction of embryonic turning. Nature 381:155-58
29. Concha ML, Burdine RD, Russell C, Schier AF, Wilson SW 2000. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28:399-409
30. Conlon FL, Barth KS, Robertson EJ. 1991. A novel retrovirally induced embryonic lethal mutation in the mouse: assessment of the developmental fate of embryonic stem cells homozygous for the 413.d proviral integration. Development 111:969-81
31. Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, et al. 1994. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 120:1919-28
32. Constam DB, Robertson EJ. 2000a. SPC4/ PACE4 regulates a TGFbeta signaling network during axis formation. Genes Dev. 14: 1146-55
33. Constam DB, Robertson EJ. 2000b. Tissue-specific requirements for the proprotein convertase Furin/SPC1 during embryonic turning and heart looping. Development 127: 245-54
34. Cordenonsi M, Dupont S, Maretto S, Inginga A, Imbriano C, Piccolo S. 2003. Links between tumor suppressors: p53 is required for TGF-beta gene responses by cooperating with Smads. Cell 113:301-14
35. Ding JX, Yang L, Yan YT, Chen A, Desai N, et al. 1998. Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395:702-7
36. Dougan ST, Warga RM, Kane DA, Schier AF, Talbot WS. 2003. The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm. Development 130:1837-51
37. Eimon PM, Harland RM. 2002. Effects of heterodimerization and proteolytic processing on Derriere and Nodal activity: implications for mesoderm induction in Xenopus. Development 129:3089-103
38. Episkopou V, Arkell R, Timmons PM, Walsh JJ, Andrew RL, Swan D. 2001. Induction of the mammalian node requires Arkadia function in the extraembryonic lineages. Nature 410:825-30
39. Erter CE, Solnica-Krezel L, Wright CVE. 1998. Zebrafish nodal-related 2 encodes an early mesendodermal inducer signaling from the extraembryonic yolk syncytial layer. Dev. Biol. 204:361-72
40. Essner JJ, Branford WW, Zhang J, Yost HJ. 2000. Mesendoderm and left-right brain, heart and gut development are differentially regulated by pitx2 isoforms. Development 127:1081-93
41. Faucourt M, Houliston E, Besnardeau L, Kimelman D, Lepage T. 2001. The pitx2 homeobox protein is required early for en doderm formation and nodal signaling. Dev. Biol. 229:287-306
42. Faure S, Lee MA, Keller T, ten Dijke P, Whitman M. 2000. Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development. Development 127: 2917-31
43. Feldman B, Concha ML, Saude L, Parsons MJ, Adams RJ, et al. 2002. Lefty antagonism of squint is essential for normal gastrulation. Curr. Biol. 12:2129-35
44. Feldman B, Dougan ST, Schier AF, Talbot WS. 2000. Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish. Curr. Biol. 10:531-34
45. Feldman B, Gates MA, Egan ES, Dougan ST, Rennebeck G, et al. 1998. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395: 181-85
46. Fujiwara T, Dehart DB, Sulik KK, Hogan BL. 2002. Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse. Development 129:4685-96
47. Gaio U, Schweickert A, Fischer A, Garratt AN, Muller T, et al. 1999. A role of the cryptic gene in the correct establishment of the left-right axis. Curr. Biol. 9:1339-42
48. Germain S, Howell M, Esslemont GM, Hill CS. 2000. Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev. 14:435-51
49. Gray PC, Harrison CA, Vale W. 2003. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc. Natl. Acad. Sci. USA 100:193-98
50. Green J. 2002. Morphogen gradients, positional information, and Xenopus: interplay of theory and experiment. Dev. Dyn. 225:392-408
51. Gritsman K, Talbot WS, Schier AF. 2000. Nodal signaling patterns the organizer. Development 127:921-32
52. Gritsman K, Zhang J, Cheng S, Heckscher E, Talbot WS, Schier AF. 1999. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97:121-32
53. Gu ZY, Reynolds EM, Song JH, Lei H, Feijen A, et al. 1999. The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 126:2551-61
54. Gurdon JB, Bourillot PY. 2001. Morphogen gradient interpretation. Nature 413:797-803
55. Hamada H, Meno C, Watanabe D, Saijoh Y. 2002. Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet. 3:103-13
56. Hashimoto-Partyka MK, Yuge M, Cho KW. 2003. Nodal signaling in Xenopus gastrulae is cell-autonomous and patterned by beta-catenin. Dev. Biol. 253:125-38
57. Hatta K, Kimmel CB, Ho RK, Walker C. 1991. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350:339-41
58. Heisenberg CP, Nusslein-Volhard C. 1997. The function of silberblick in the positioning of the eye anlage in the zebrafish embryo. Dev. Biol. 184:85-94
59. Hoodless PA, Pye M, Chazaud C, Labbe E, Attisano L, et al. 2001. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15:1257-71
60. Hyde CE, Old RW. 2000. Regulation of the early expression of the Xenopus nodal-related 1 gene, Xnr1. Development 127:1221-29
61. Iratni R, Van YT, Chen CH, Ding JX, Zhang Y, et al. 2002. Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1. Science 298:1996-99
62. Jones CM, Armes N, Smith JC. 1996. Signalling by TGF-beta family members: short-range effects of Xnr-2 and BMP-4 contrast with the long-range effects of activin. Curr. Biol. 6:1468-75
63. Jones CM, Kuehn MR, Hogan BL, Smith JC, Wright CV. 1995. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121: 3651-62
64. Kato Y, Habas R, Katsuyama Y, Naar AM, He X. 2002. A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 418:641-46
65. Kikuchi Y, Trinh LA, Reiter JF, Alexander J, Yelon D, Stainier DY 2000. The zebrafish bonnie and clyde gene encodes a Mix family homeodomain protein that regulates the generation of endodermal precursors. Genes Dev. 14:1279-89
66. Kimmel CB, Warga RM, Schilling TF. 1990. Origin and organization of the zebrafish fate map. Development 108:581-94
67. Kinoshita N, Minshull J, Kirschner MW. 1995. The identification of two novel ligands of the FGF receptor by a yeast screening method and their activity in Xenopus development. Cell 83:621-30
68. Kofron M, Demel T, Xanthos J, Lohr J, Sun B, et al. 1999. Mesoderm induction in Xenopus is a zygotic event regulated by maternal VegT via TGFbeta growth factors. Development 126:5759-70
69. Krebs LT, Iwai N, Nonaka S, Welsh IC, Lan Y, et al. 2003. Notch signaling regulates left-right asymmetry determination by inducing Nodal expression. Genes Dev. 17:1207-12
70. Kumar A, Novoselov V, Celeste AJ, Wolfman NM, ten Dijke P, Kuehn MR. 2001. Nodal signaling uses activin and transforming growth factor-beta receptor-regulated Smads. J. Biol. Chem. 276:656-61
71. Langheinrich U, Hennen E, Stott G, Vacun G. 2002. Zebrafish as a model organism for the identification and characterization of drugs and genes affecting p53 signaling. Curr. Biol. 12:2023-28
72. Lee MA, Heasman J, Whitman M. 2001. Timing of endogenous activin-like signals and regional specification of the Xenopus embryo. Development 128:2939-52
73. Levin M, Johnson RL, Stern CD, Kuehn M, Tabin C. 1995. A molecular pathway determining left-right asymmetry in chick embryogenesis. Cell 82:803-14
74. Long S, Ahmad N, Rebagliati M. 2003. The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development 130:2303-16
75. Lowe LA, Supp DM, Sampath K, Yokoyama T, Wright CV, et al. 1996. Conserved left-right asymmetry of nodal expression and alterations in murine situs inversus. Nature 381:158-61
76. Lowe LA, Yamada S, Kuehn MR. 2001. Genetic dissection of nodal function in patterning the mouse embryo. Development 128:1831-43
77. Lu CC, Brennan J, Robertson EJ. 2001. From fertilization to gastrulation: axis formation in the mouse embryo. Curr. Opin. Genet. Dev. 11:384-92
78. Mathieu J, Barth A, Rosa FM, Wilson SW, Peyrieras N. 2002. Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development. Development 129:3055-65
79. Meinhardt H. 2001. Organizer and axes formation as a self-organizing process. Int. J. Dev. Biol. 45:177-88
80. Meno C, Gritsman K, Ohishi S, Ohfuji Y, Heckscher E, et al. 1999. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4:287-98
81. Meno C, Ito Y, Saijoh Y, Matsuda Y, Tashiro K, et al. 1997. Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells 2:513-24
82. Meno C, Saijoh Y, Fujii H, Ikeda M, Yokoyama T, et al. 1996. Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature 381:151-55
83. Meno C, Shimono A, Saijoh Y, Yashiro K, Mochida K, et al. 1998. lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94:287-97
84. Meno C, Takeuchi J, Sakuma R, KoshibaTakeuchi K, Ohishi S, et al. 2001. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev. Cell 1:127-38
85. Mercola M, Levin M. 2001. Left-right asymmetry determination in vertebrates. Annu. Rev. Cell Dev. Biol. 17:779-805
86. Niederlander C, Walsh JJ, Episkopou V, Jones CM. 2001. Arkadia enhances nodal-related signalling to induce mesendoderm. Nature 410:830-34
87. Nomura M, Li E. 1998. Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393:786-90
88. Nonaka S, Shiratori H, Saijoh Y, Hamada H. 2002. Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96-99
89. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, et al. 1998. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95:829-37
90. Norris DP, Brennan J, Bikoff EK, Robertson EJ. 2002. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129:3455-68
91. Oh SP, Li E. 1997. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 11:1812-26
92. Osada SI, Saijoh Y, Frisch A, Yeo CY, Adachi H, et al. 2000. Activin/nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1. Development 127:2503-14
93. Perea-Gomez A, Vella FD, Shawlot W, Oulad-Abdelghani M, Chazaud C, et al. 2002. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3:745-56
94. Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, et al. 1999. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397: 707-10
95. Piedra ME, Ros MA. 2002. BMP signaling positively regulates Nodal expression during left right specification in the chick embryo. Development 129:3431-40
96. Pogoda HM, Solnica-Krezel L, Driever W, Meyer D. 2000. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr. Biol. 10:1041-49
97. Przemeck GKH, Heinzmann U, Beckers J, de Angelis MH. 2003. Node and midline defects are associated with left-right development in Deltal mutant embryos. Development 130:3-13
98. Rankin CT, Bunton T, Lawler AM, Lee SJ. 2000. Regulation of left-right patterning in mice by growth/differentiation factor-1. Nat. Genet. 24:262-65
99. Raya A, Kawakami Y, Rodriguez-Esteban C, Buscher D, Koth CM, et al. 2003. Notch activity induces Nodal expression and mediates the establishment of left-right asymmetry in vertebrate embryos. Genes Dev. 17:R13-18
100. Rebagliati MR, Toyama R, Fricke C, Haffter P, Dawid IB. 1998a. Zebrafish nodal-related genes are implicated in axial patterning and establishing left-right asymmetry. Dev. Biol. 199:261-72
101. Rebagliati MR, Toyama R, Haffter P, Dawid IB. 1998b. cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl. Acad. Sci. USA 95:9932-37
102. Reissmann E, Jornvall H, Blokzijl A, Andersson O, Chang C, et al. 2001. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes Dev. 15:2010-22
103. Saijoh Y, Adachi H, Sakuma R, Yeo CY, Yashiro K, et al. 2000. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol. Cell 5:35-41
104. Saijoh Y, Oki S, Ohishi S, Hamada H. 2003. Left-right patterning of the mouse lateral plate requires nodal produced in the node. Dev. Biol. 256:161-73
105. Sakuma R, Ohnishi Y, Meno C, Fujii H, Juan H, et al. 2002. Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion. Genes Cells 7:401-12
106. Sampath K, Rubinstein AL, Cheng AM, Liang JO, Fekany K, et al. 1998. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395:185-89
107. Schier AF, Neuhauss SC, Helde KA, Talbot WS, Driever W. 1997. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124:327-42
108. Schier AF, Shen MM. 2000. Nodal signalling in vertebrate development. Nature 403:385-89
109. Schier AF, Talbot WS. 2001. Nodal signaling and the zebrafish organizer. Int. J. Dev. Biol. 45:289-97
110. Schiffer SG, Foley S, Kaffashan A, Hronowski X, Zichittella AE, et al. 2001. Fucosylation of Cripto is required for its ability to facilitate nodal signaling. J. Biol. Chem. 276:37769-78
111. Schlange T, Arnold HH, Brand T. 2002. BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo. Development 129:3421-29
112. Schlange T, Schnipkoweit I, Andree B, Ebert A, Zile MH, et al. 2001. Chick CFC controls Lefty1 expression in the embryonic midline and nodal expression in the lateral plate. Dev. Biol. 234:376-89
113. Shen MM, Schier AF. 2000. The EGF-CFC gene family in vertebrate development. Trend Genet. 16:303-9
114. Shi Y, Massague J. 2003. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685-700
115. Shimizu T, Yamanaka Y, Ryu SL, Hashimoto H, Yabe T, et al. 2000. Cooperative roles of Bozozok/Dharma and Nodal-related proteins in the formation of the dorsal organizer in zebrafish. Mech. Dev. 91:293-303
116. Shiratori H, Sakuma R, Watanabe M, Hashiguchi H, Mochida K, et al. 2001. Two-step regulation of left-right asymmetric expression of Pitx2: initiation by nodal signaling and maintenance by Nkx2. Mol. Cell 7:137-49
117. Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, et al. 1998. The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev. 12:107-19
118. Sirotkin HI, Gates MA, Kelly PD, Schier AF, Talbot WS. 2000. Fast1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol. 10:1051-54
119. Smith JC. 1995. Mesoderm-inducing factors and mesodermal patterning. Curr. Opin. Cell Biol. 7:856-61
120. Smith WC, McKendry R, Ribisi S Jr, Harland RM. 1995. A nodal-related gene defines a physical and functional domain within the Spemann organizer. Cell 82:37-46
121. Song J, Oh SP, Schrewe H, Nomura M, Lei H, et al. 1999. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 213:157-69
122. Stainier DY. 2002. A glimpse into the molecular entrails of endoderm formation. Genes Dev. 16:893-907
123. Strahle U, Jesuthasan S, Blader P, Garcia-Villalba P, Hatta K, Ingham PW. 1997. one-eyed pinhead is required for development of the ventral midline of the zebrafish (Danio rerio) neural tube. Genes Funct. 1:131-48
124. Takahashi S, Yokota C, Takano K, Tanegashima K, Onuma Y, et al. 2000. Two novel nodal-related genes initiate early inductive events in Xenopus Nieuwkoop center. Development 127:5319-29
125. Tanegashima K, Yokota C, Takahashi S, Asashima M. 2000. Expression cloning of Xantivin, a Xenopus lefty/antivin-related gene, involved in the regulation of activin signaling during mesoderm induction. Mech. Dev. 99:3-14
126. Thisse B, Wright CV, Thisse C. 2000. Activin-and Nodal-related factors control antero-posterior patterning of the zebrafish embryo. Nature 403:425-28
127. Thisse C, Thisse B. 1999. Antivin, a novel and divergent member of the TGFbeta superfamily, negatively regulates mesoderm induction. Development 126:229-40
128. Tremblay KD, Hoodless PA, Bikoff EK, Robertson EJ. 2000. Formation of the definitive endoderm in mouse is a Smad2-dependent process. Development 127:3079-90
129. Turing AM. 1952. The chemical basis of morphogenesis. Philos. Trans. R. Soc. 237:37-72
130. Ulloa L, Creemers JW, Roy S, Liu S, Mason J, Tabibzadeh S. 2001. Lefty proteins exhibit unique processing and activate the MAPK pathway. J. Biol. Chem. 276:21387-96
131. Varlet I, Collignon J, Robertson EJ. 1997.Nodal expression in the primitive endoderm is required for the specification of the anterior axis during mouse gastrulation. Development 124:1033-44
132. Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ. 1998. Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 92:797-808
133. Warga RM, Nusslein-Volhard C. 1999. Origin and development of the zebrafish endoderm. Development 126:827-38
134. Watanabe D, Saijoh Y, Nonaka S, Sasaki G, Ikawa Y, et al. 2003. The left-right determinant Inversin is a component of node monocilia and other 9+0 cilia. Development 130:1725-34
135. Weinstein M, Yang X, Li CL, Xu XL, Gotay J, Deng CX. 1998. Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc. Natl. Acad. Sci. USA 95:9378-83
136. Whitman M. 2001. Nodal signaling in early vertebrate embryos: themes and variations. Dev. Cell 1:605-17
137. Xanthos JB, Kofron M, Wylie C, Heasman J. 2001. Maternal VegT is the initiator of a molecular network specifying endoderm in Xenopus laevis. Development 128:167-80
138. Yabe SI, Tanegashima K, Haramoto Y, Takahashi S, Fujii T, et al. 2003. FRL-1, a member of the EGF-CFC family, is essential for neural differentiation in Xenopus early development. Development 130:2071-81
139. Yamamoto M, Meno C, Sakai Y, Shiratori H, Mochida K, et al. 2001. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev. 15:1242-56
140. Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, et al. 2003. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130:1795-804
141. Yan YT, Gritsman K, Ding JX, Burdine RD, Corrales JD, et al. 1999. Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev. 13:2527-37
142. Yan YT, Liu JJ, Luo Y, Chaosu E, Haltiwanger RS, et al. 2002. Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway. Mol. Cell Biol. 22:4439-49
143. Yang X, Li CL, Xu XL, Deng CX. 1998. The tumor suppressor SMAD4/DPC4 is essential for epiblast proliferation and mesoderm induction in mice. Proc. Natl. Acad. Sci. USA 95:3667-72
144. Yeo C, Whitman M. 2001. Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms. Mol. Cell 7:949-57
145. Yokota C, Kofron M, Zuck M, Houston DW, Isaacs H, et al. 2003. A novel role for a nodal-related protein; Xnr3 regulates convergent extension movements via the FGF receptor. Development 130:2199-212
146. Zhou X, Sasaki H, Lowe L, Hogan BL, Kuehn MR. 1993. Nodal is a novel TGF-beta-like gene expressed in the mouse node during gastrulation. Nature 361:543-47