mDpr2、zhmg2l1、zppm1a在胚胎发育过程中的功能研究
|
摘要
TGFβ/Nodal信号通路是影响胚胎发育的几个重要的信号通路之一。相比于其他信号通路,Nodal信号通路对于胚胎的中内胚层的诱导起到关键的作用。本文选取了三个与TGFβ信号通路相关的基因,即小鼠Dapper2,斑马鱼hmg2l1和ppm1a,研究其时空表达谱及功能,以加深对脊椎动物胚胎发育机理的了解。
我们曾报道斑马鱼Dapper2通过降解Nodal受体而抑制胚胎中胚层的发育,但哺乳动物Dapper2未见报导。鉴于Dapper2对于胚胎中胚层发育的重要性,本文首先克隆出小鼠Dapper2基因,并研究其时空表达谱,发现它在体节形成期后在体节、耳泡、神经顶板、肠等组织中特异性表达。荧光酶报告实验显示小鼠Dapper2可以抑制TGFβ信号通路活性。胚胎实验表明,在斑马鱼胚胎中过量表达小鼠Dapper2,可以抑制斑马鱼胚胎的中胚层的发育。这些实验结果都说明,小鼠Dapper2和斑马鱼dapper2在调节TGFβ信号和胚胎发育方面具有保守性。
以斑马鱼Dapper2为诱饵,通过酵母双杂交筛选,鉴定出与斑马鱼Dapper2互作的Hmg2l1。在哺乳动物细胞中,转染斑马鱼Hmg2l1可以抑制β-catenin介导的Wnt信号,也可以增强Smad2/3介导的TGFβ/Nodal信号。在斑马鱼oep突变体中,过量表达hmg2l1,可以导致突变体胚胎的头部缺失。关于hmg2l1影响斑马鱼发育的作用机理还需要更进一步的研究。
斑马鱼Ppm1a是镁离子依赖性的丝氨酸/苏氨酸磷酸酶,它可以使磷酸化的Smad2/3去磷酸化,从而抑制TGFβ/Nodal信号通路活性。本实验发现,斑马鱼ppm1a是全身性表达的母源基因。在斑马鱼胚胎中过量表达ppm1a,可以抑制背部中胚层组织的发育。过量表达ppm1a还可以缓解由注射Smad2的MH2结构域蛋白或smad3b mRNA而引起的背部化表型;Smad2的MH2结构域蛋白的注射也可以减轻ppm1a对于背部中胚层组织发育的抑制作用。这些结果表明Ppm1a通过影响Smad2/3来下调TGFβ/Nodal信号,从而影响胚胎背部中胚层的发育。
本研究表明,Dapper2、Hmg2l1和Ppm1a都是TGFβ/Nodal的负调控因子,可能均参与控制脊椎动物胚胎的背部发育。这些数据为了解TGFβ/Nodal信号的转导调控机理和对胚胎发育的调控作用提供了新的视觉。
TGFβ/Nodal signaling pathway is one of the most important signaling pathways in the development of embryos. Compared with other signals, TGFβ/Nodal plays a key role in the induction of mesendoderm. Here, my work focused on three genes, mouse Dapper2, zebrafish hmg2l1 and ppm1a, which were all related with TGFβsignaling pathway. Their expression patterns and functions were studied to further illustrate the mechanism of embryonic development.
As we have reported, zebrafish Dapper2 acted as an inhibitor of mesoderm development by promoting the degradation of Nodal receptor, however, mammalian Dapper2 has never been reported. Because of the significance of zebrafish Dapper2 in mesoderm induction, the mouse dapper2 was cloned following its homolog. The study of its spatial and temporal expression pattern showed that it expressed specifically in otic vesicle, somite,gut and roof plate of mouse embryos. In the ARE-luciferase reporter assay, mouse Dapper2 can inhibit the activity of TGFβpathway. The overexpression of mouse Dapper2 in zebrafish embryos induced the reduction of mesoderm. All of the results suggested that the effects of Dapper2 in regulating TGFβsignal and zebrafish embryonic development were conserved between zebrafish and mouse.
Zebrafish Hmg2l1, which was obtained by yeast two-hybridization using zebrafish Dapper2 as bait, can interact with zebrafish Dapper2. It repressed Wnt signal dependent onβ-catenin and activated TGFβ/Nodal signaling pathway transduced by Smad2/3. The overexpression of hmg2l1 led to the absence of head structure in oep mutant. More work is still needed to explain the mechanism.
Zebrafish Ppm1a, a Mg2+-dependent serine/threonine phosphatase, was identified as a Smad2/3-specific phosphatase. It down-regulated TGFβ/Nodal signal by dephosphorylating the activated Smad2/3. Demonstrated by in situ hybridization, zebrafish ppm1a was a maternal gene and expressed throughout the embryos. In the zebrafish, overexpression of ppm1a can inhibit the development of dorsal mesoderm,and the abnormal phenotype can be rescued by injection of the MH2 domain of Smad2 protein. Furthermore, overexpression of ppm1a can rescued the dorsalized phenotype caused by the injection of Smad2-MH2 protein or smad3b mRNA. These results revealed that Ppm1a can down-regulate TGFβ/Nodal signal and affect the development of dorsal mesoderm by interacting with Smad2/3.
My work showed that Dapper2, Hmg2l1 and Ppm1a were negative regulators of TGFβ/Nodal signal and they perhaps regulated the development of dorsal structure in vertebrate embryos. These data give some new insights on the mechanism of TGFβ/Nodal transduction and in regulation of embryonic development.
我们曾报道斑马鱼Dapper2通过降解Nodal受体而抑制胚胎中胚层的发育,但哺乳动物Dapper2未见报导。鉴于Dapper2对于胚胎中胚层发育的重要性,本文首先克隆出小鼠Dapper2基因,并研究其时空表达谱,发现它在体节形成期后在体节、耳泡、神经顶板、肠等组织中特异性表达。荧光酶报告实验显示小鼠Dapper2可以抑制TGFβ信号通路活性。胚胎实验表明,在斑马鱼胚胎中过量表达小鼠Dapper2,可以抑制斑马鱼胚胎的中胚层的发育。这些实验结果都说明,小鼠Dapper2和斑马鱼dapper2在调节TGFβ信号和胚胎发育方面具有保守性。
以斑马鱼Dapper2为诱饵,通过酵母双杂交筛选,鉴定出与斑马鱼Dapper2互作的Hmg2l1。在哺乳动物细胞中,转染斑马鱼Hmg2l1可以抑制β-catenin介导的Wnt信号,也可以增强Smad2/3介导的TGFβ/Nodal信号。在斑马鱼oep突变体中,过量表达hmg2l1,可以导致突变体胚胎的头部缺失。关于hmg2l1影响斑马鱼发育的作用机理还需要更进一步的研究。
斑马鱼Ppm1a是镁离子依赖性的丝氨酸/苏氨酸磷酸酶,它可以使磷酸化的Smad2/3去磷酸化,从而抑制TGFβ/Nodal信号通路活性。本实验发现,斑马鱼ppm1a是全身性表达的母源基因。在斑马鱼胚胎中过量表达ppm1a,可以抑制背部中胚层组织的发育。过量表达ppm1a还可以缓解由注射Smad2的MH2结构域蛋白或smad3b mRNA而引起的背部化表型;Smad2的MH2结构域蛋白的注射也可以减轻ppm1a对于背部中胚层组织发育的抑制作用。这些结果表明Ppm1a通过影响Smad2/3来下调TGFβ/Nodal信号,从而影响胚胎背部中胚层的发育。
本研究表明,Dapper2、Hmg2l1和Ppm1a都是TGFβ/Nodal的负调控因子,可能均参与控制脊椎动物胚胎的背部发育。这些数据为了解TGFβ/Nodal信号的转导调控机理和对胚胎发育的调控作用提供了新的视觉。
TGFβ/Nodal signaling pathway is one of the most important signaling pathways in the development of embryos. Compared with other signals, TGFβ/Nodal plays a key role in the induction of mesendoderm. Here, my work focused on three genes, mouse Dapper2, zebrafish hmg2l1 and ppm1a, which were all related with TGFβsignaling pathway. Their expression patterns and functions were studied to further illustrate the mechanism of embryonic development.
As we have reported, zebrafish Dapper2 acted as an inhibitor of mesoderm development by promoting the degradation of Nodal receptor, however, mammalian Dapper2 has never been reported. Because of the significance of zebrafish Dapper2 in mesoderm induction, the mouse dapper2 was cloned following its homolog. The study of its spatial and temporal expression pattern showed that it expressed specifically in otic vesicle, somite,gut and roof plate of mouse embryos. In the ARE-luciferase reporter assay, mouse Dapper2 can inhibit the activity of TGFβpathway. The overexpression of mouse Dapper2 in zebrafish embryos induced the reduction of mesoderm. All of the results suggested that the effects of Dapper2 in regulating TGFβsignal and zebrafish embryonic development were conserved between zebrafish and mouse.
Zebrafish Hmg2l1, which was obtained by yeast two-hybridization using zebrafish Dapper2 as bait, can interact with zebrafish Dapper2. It repressed Wnt signal dependent onβ-catenin and activated TGFβ/Nodal signaling pathway transduced by Smad2/3. The overexpression of hmg2l1 led to the absence of head structure in oep mutant. More work is still needed to explain the mechanism.
Zebrafish Ppm1a, a Mg2+-dependent serine/threonine phosphatase, was identified as a Smad2/3-specific phosphatase. It down-regulated TGFβ/Nodal signal by dephosphorylating the activated Smad2/3. Demonstrated by in situ hybridization, zebrafish ppm1a was a maternal gene and expressed throughout the embryos. In the zebrafish, overexpression of ppm1a can inhibit the development of dorsal mesoderm,and the abnormal phenotype can be rescued by injection of the MH2 domain of Smad2 protein. Furthermore, overexpression of ppm1a can rescued the dorsalized phenotype caused by the injection of Smad2-MH2 protein or smad3b mRNA. These results revealed that Ppm1a can down-regulate TGFβ/Nodal signal and affect the development of dorsal mesoderm by interacting with Smad2/3.
My work showed that Dapper2, Hmg2l1 and Ppm1a were negative regulators of TGFβ/Nodal signal and they perhaps regulated the development of dorsal structure in vertebrate embryos. These data give some new insights on the mechanism of TGFβ/Nodal transduction and in regulation of embryonic development.
引文
Agathon A, Thisse B, Thisse C. 2001. Morpholino knock-down of antivin1 and antivin2 upregulates nodal signaling. Genesis 30:178-182
Agius E, Oelgeschlager M, Wessely O, Kemp C, DeRobertis E M. 2000. Endodermal Nodal-related signals and mesoderm induction in Xenopus. Development 127:1173-1183
Audic Y, Boyle B, Slevin M, and Hartley R S. 2001. Cyclin E morpholino delays embryogenesis in Xenopus. Genesis 30:107-109
Bauer H, Lele Z, Rauch G J, Geisler R, and Hammerschmidt M. 2001. The type I serine/threonine kinase receptor Alk8/Lost-a-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development 128:849-858
Beddington R S. 1994. Induction of a second neural axis by the mouse node. Development 120:613-620
Bell E, Munoz-Sanjuan I, Altmann C R, Vonica A, Brivanlou A H. 2003. Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development 130:1381-1389
Belo J A, Bachiller D, Agius E, Kemp C, Borges A C, et al. 2000. Cerberus-like is a secreted
BMP and nodal antagonist not essential for mouse development. Genesis 26:265-270
Bertocchini F, Stern C D. 2002. The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling. Dev. Cell 3:735-744
Brennan J, Lu C C, Norris D P, Rodriguez T A, Beddington R S, Robertson E J. 2001. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411:965-969
Burdine R D, Schier A F. 2000. Conserved and divergent mechanisms in left-right axis formation. Genes Dev. 14:763-776
Bustin M. 2001. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem. Sci. 26:152-153
Capdevila J, Vogan K J, Tabin C J, Belmonte J C I. 2000. Mechanisms of left-right determination in vertebrates. Cell 101:9-21
Carmany-Rampey A, Schier A F. 2001. Single cell internalization during zebrafish gastrulation. Curr. Biol. 11:1261-1265
Cavallo R A, Cox R T, Moline M M, et al. 1998. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395:604–608
Chen H B, Shen J, Ip Y T, Xu L. 2006. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 20:648-653
Chen S, Kimelman D. 2000. The role of the yolk syncytial layer in germ layer patterning in zebrafish. Development 127:4681-4689
Chen X, Rubock M J, and Whitman M. 1996. A transcriptional partner for Mad proteins in TGFβ signalling. Nature 383:691-696
Chen Y, Schier A F. 2001. The zebrafish Nodal signal Squint functions as a morphogen. Nature 411:607-610
Chen Y, Schier A F. 2002. Lefty proteins are long-range inhibitors of squint-mediated nodal signaling. Curr. Biol. 12:2124-2128
Cheyette B N, Waxman J S, Miller J R, Takemaru K, Sheldahl L C. 2002. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev. Cell 2:449-461
Concha M L, Burdine R D, Russell C, Schier A F, Wilson S W. 2000. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28:399-409
Conlon F, Lyons K, Takaesu N, Barth K, Kispert A, Hermann B, and Robertson E. 1994. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 129:1919-1928
Coonrod S A, Bolling L C, Wright P W, Visconti P E, and Herr J C. 2001. A morpholino phenocopy of the mouse MOS mutation. Genesis 30:198-200
Corey D R, Abrams J M. 2001. Morpholino antisense oligonucleotides: tools for investigating vertebrate development. Genome Bio. 2:10151-10153
De Robertis E M, Larrain J, Oelgeschlager M, Wessely O. 2000. The establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nat. Rev. Genet. 1:171-181
Ding J X, Yang L, Yan Y T, Chen A, Desai N, et al. 1998. Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395:702-707
Dougan S T, Warga R M, Kane D A, Schier A F, Talbot W S. 2003. The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm. Development 130:1837–1851
Dunham I, Shimizu N, Roe B A, et al. 1999. The DNA sequence of human chromosome 22. Nature 402:489–495
Erter C E, Solnica-Krezel L, and Wright C V E. 1998. Zebrafish nodal related-2 encodes an early mesendodermal inducer signaling from the extraembryonic yolk syncytial layer. Dev. Biol. 204:361-372
Feldman B, Concha M L, Saude L, Parsons M J, Adams R J, et al. 2002. Lefty antagonism of squint is essential for normal gastrulation. Curr. Biol. 12:2129-2135
Feldman B, Dougan S T, Schier A F, Talbot W S. 2000. Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish. Curr. Biol. 10:5315-5334
Feldman B, Gates M A, Egan E S, Dougan S T, Rennebeck G, et al. 1998. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395:181-185
Feldman B, Gates M A, Egan E S, Dougan S T, Rennebeck G, Sirotkin H I, Rebagliati M R, Toyama R, Haffter P, and Dawid I B. 1998b. Cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl. Acad. Sci. USA 95:9932-9937
Gaio U, Schweickert A, Fischer A, Garratt A N, Muller T, Ozcelik C, Lankes W, Strehle M, Britsch S, Blum M, Birchmeier C. 1999. A role of the cryptic gene in the correct establishment of the leftright axis. Curr. Biol. 9:1339-1342
Gallego M, and Virshup D M. 2005. Protein serine/threonine phosphatases: life, death, and sleeping. Curr. Opin. Cell Biol. 17:197-202
Gloy J, Hikasa H, Sokol S Y. 2002. Frodo interacts with Dishevelled to transducer Wnt signals. Nat. Cell Biol. 4:351-357
Gray P C, Harrison C A, Vale W. 2003. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc. Natl. Acad. Sci. USA 100:193-198
Green J. 2002. Morphogen gradients, positional information, and Xenopus: interplay of theory and experiment. Dev. Dyn. 225:392-408
Green J B, Smith J C. 1990. Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate. Nature 347:391-394
Gritsman K, Talbot W S, Schier A F. 2000. Nodal signaling patterns the organizer. Development 127:921-932
Gritsman K, Zhang J, Cheng S, Heckscher E, Talbot W S, Schier A F. 1999. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97:121-132
Gurdon JB, Bourillot P Y. 2001. Morphogen gradient interpretation. Nature 413:797-803
Gurdon J B, Harger P, Mitchell A, Lemaire P. 1994. Activin signaling and response to a morphogen gradient. Nature 371:487-492
Gu Z Y, Nomura M, Simpson B B, Lei H, Feijen A, van den Rijnden-van Raaij J, Donahoe P K, and Li E. 1998. The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev. 12:844-857
Hamada H, Meno C, Watanabe D, Saijoh Y. 2002. Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet. 3:103-113
Harland R, Gerhart J. 1997. Formation and function of Spemann’s organizer. Annu. Rev. Cell Dev. Biol. 13:611-667.
Hatta K, Kimmel C B, Ho R K, Walker C. 1991. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350:339-341
Heasman J, Kofron M, and Wylie C. 2000. Beta-catenin signaling activity dissected in the early Xenopus embryo: A novel antisense approach. Dev. Biol. 222:124-134
Hill C. 2001. TGFβ signaling pathways in early Xenopus development. Curr. Opin. Genet. Dev. 11:533-540
Hoodless P A, Pye M, Chazaud C, Labbe E, Attisano L, Rossant J, Wrana J L. 2001. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15:1257-1271
Howard E W, Newman L A, Oleksyn D W, Angerer R C, and Angerer L M. 2001. SpKrl: A direct target of beta-catenin regulation required for endoderm differentiation in sea urchin embryos. Development 128:365-375
Huang H C, Murtaugh L C, Vize P D, and Whitman M. 1995. Identification of a potential regulator of early transcriptional responses to mesoderm inducers in the frog embryo. EMBO J. 14:5965-5973
Jones C M, Kuehn M R, Hogan B L, Smith J C, Wright C V. 1995. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121:3651-3662
Joseph E M, Melton D A. 1997. Xnr4: a Xenopus nodal-related gene expressed in the Spemann organizer. Dev Biol 184:367-372
Katoh M, Katoh M. 2003. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int. J. Oncol. 22:907-913
Katoh M, Katoh M. 2005. Identification and characterization of rat Dact1 and Dact2 genes in silico. Int. J. Mol. Med. 15:1045-1049
Kidder G M. 1992. The genetic program for preimplantation development. Dev. Genet. 13:319-325
Kimmel C B, Ballard W W, Kimmel S R, Ullmann B, and Schilling T F. 1995. Stages of embryonic development of the zebrafish. Dev. Dyn. 203:253-310
Kos R, Reedy M V, Johnson R L, and Erickson C A. 2001. The winged-helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 128:1467-1479
Labbe′ E, Silvestri C, Hoodless P A, Wrana J L, and Attisano L. 1998. Smad2 and Smad3 positively and negatively regulate TGFbeta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol. Cell 2:109-120
Lee K J, Mendelsohn M, Jessell T M. 1998. Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev. 12:3394-3407
Levanon D, Goldstein R E, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y. 1998. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl. Acad. Sci. USA 95:11590–11595
Lin X, Duan X, Liang Y, Su Y, Wrighton K H, Long J, Hu M, Davis C M, Wang J, Brunicardi F C, Shi Y G, Chen Y G, Meng A, Feng X H. 2006. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell Scheduled publishing date: June 2nd issue
Long S, Ahmad N, Rebagliati M. 2003. The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development 130:2303-2316
Lou R, An M, Arduini B L, Henion P D. 2001. Specific pan-neural crest expression of zebrafish crestin throughout embryonic development. Dev. Dyn. 220:169-174
Lowe L A,Yamada S, Kuehn M R. 2001. Genetic dissection of nodal function in patterning the mouse embryo. Development 128:1831-1843
Lu C C, Brennan J, Robertson E J. 2001. From fertilization to gastrulation: axis formation in the mouse embryo. Curr. Opin. Genet. Dev. 11:384-392
Manzanares M, and Krumlauf R. 2000. Raising the roof. Nature 403:720-721
Massague′ J. 1998. TGFβ Signal Transduction. Annu. Rev. Biochem. 67:753-791
Massague′ J, and Wotton D. 2000. Transcriptional control by the TGF/Smad signaling system. EMBO J. 19:1745-1754
Meno C, Gritsman K, Ohishi S, Ohfuji Y, Heckscher E, Mochida K, Shimono A, Kondoh H, Talbot W S, Robertson E J, Schier A F, Hamada H. 1999. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4:287-298
Meno C, Saijoh, Y, Fujii H, Ikeda M, Yokoyama T, Yokoyama M, Toyoda Y, Hamada H. 1996. Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature 381:151-155
Meno C, Takeuchi J, Sakuma R, Koshiba-Takeuchi K, Ohishi S, Saijoh Y, Miyazaki J, ten Dijke P, Ogura T, Hamada H. 2001. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev. Cell 1:127-138
Mercola M, Levin M. 2001. Left-right asymmetry determination in vertebrates. Annu. Rev. Cell Dev. Biol. 17:779-805
Montero J, and Heisenberg C. 2004. Gastrulation dynamics: cells move into focus. Trends in Cell Bio. 14:620-627
Nasevicius A, and Ekker S C. 2000. Effective targeted gene “knockdown” in zebrafish. Nat. Genet. 26:216-220
Nieuwkoop P D. 1973. The organization center of the amphibian embryo: its origin, spatial organization, and morphogenetic action. Adv. Morphog. 10:1–39
Norris D P, Brennan J, Bikoff E K, Robertson E J. 2002. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129:3455-3468
Oh S P, and Li E. 1997. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 11:1812-1826
Perea-Gomez A, Vella F D, Shawlot W, Oulad-Abdelghani M, Chazaud C, Meno C, Pfister V, Chen L, Robertson E, Hamada H, Behringer R R, Ang S L. 2002. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3:745-756
Pevny L H & Lovell-Badge R. 1997. Sox genes find their feet. Curr. Opin. Genet. Dev. 7:338–344
Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis E M. 1999. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397:707-710
Pogoda H M, Solnica-Krezel L, Driever W, and Meyer D. 2000. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of Nodal signaling required for organizer formation. Curr. Biol. 10:1041-1049
Reissmann E, Jornvall H, Blokzijl A, Andersson O, Chang C, Minchiotti G, Persico M G, Ibanez C F, and Brivanlou A H. 2001. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes Dev. 15:2010-2022
Renucci A, Lemarchandel V, and Rosa F. 1996. An activated form of type I serine/threonine kinase receptor TARAM-A reveals a specific signalling pathway involved in fish head organizer formation. Development 122:3735-3743
Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destree O, Clevers H. 1998. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395:608–612
Ross J J, Shimmi O, Vilmos P, Petryk A, Kim H, Gaudenz K, Hermanson S, Ekker S C, O’Connor M B, and Marsh J L. 2001. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410:479-483
Saijoh Y, Adachi H, Sakuma R, Yeo C Y, Yashiro K, Watanabe M, Hashiguchi H, Mochida K, Ohishi S, Kawabata M, Miyazono K, Whitman M, Hamada H. 2000. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol. Cell 5:35-47
Sampath K, Rubinstein A L, Cheng A M, Liang J O, Fekany K, Solnica-Krezel L, Korzh V, Halpern M E, and Wright C V. 1998. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395:185-189
Satou Y, Imai K S, and Satoh N. 2001. Action of morpholinos in Ciona embryos. Genesis 30:103-106
Schier A F. 2001. Axis formation and patterning in zebrafish. Current Opinion in Genetics & Development 11:393-404
Schier A F. 2003. Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 19:589-621
Schier A F, Neuhauss S C, Helde K A, Talbot W S, Driever W. 1997. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124:327-342
Schier A F, Shen M M. 2000. Nodal signaling in vertebrate development. Nature 403:385-389
Schier A F, and Talbot W S. 1998. Zebrafish organizer development and germ-layer formation require nodal- related signals. Nature 395:181-185
Schier A F, and Talbot W S. 2001. Nodal signaling and the zebrafish organizer. Int. J. Dev. Biol. 45:289-297
Schultz R M. 1986. Molecular aspects of mammalian oocyte growth and maturation. In Experimental approaches to mammaliam embryonic development. 195-237. Cambridge University Press, England.
Schweickert A, Deissler K, Blum M, and Steinbeisser H. 2001. Pitx1 and Pitx2c are required for ectopic cement gland formation in Xenopus laevis. Genesis 30:144-148
Segawa H, Miyashita T, Hirate Y, Higashijima S, Chino N, Uyemura K, Kikuchi Y, and Okamoto H. 2001. Functional repression of Islet-2 by disruption of complex with Ldb impairs peripheral axonal outgrowth in embryonic zebrafish. Neuron 30:423-436
Seroussi E, Kedra D, Kost-Alimova M, Sandberg-Nordqvist A C, Fransson I, Jacobs J F, Fu Y, Pan H Q, Roe B A, Imreh S, Dumanski J P. 1999. TOM1 genes map to human chromosome 22q13.1 and mouse chromosome 8C1 and encode proteins similar to the endosomal proteins HGS and STAM. Genomics 57:380-388
Shen M M, and Schier A F. 2000. The EGF-CFC gene family in vertebrate development. Trends Genet. 16:303-309
Shepherd I T, Beattie C E, and Raible D W.2001. Functional analysis of zebrafish GDNF. Dev. Biol. 231:420-435
Sirotkin H I, Gates M A, Kelly P D, Schier A F, and Talbot W S. 2000. Fast1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol. 10:1051-1054
Smith J C. 1995. Mesoderm-inducing factors and mesodermal patterning. Curr. Opin. Cell Biol. 7:856-861
Song J, Oh S P, Schrewe H, Nomura M, Lei H, Okano M, Gridley T, and Li E. 1999. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 213:157-169
Spemann H, and Mangold H. 1924. Uber Induktion von Embryo-nanlagen durch Implantation artfremder Organisatoren. Arch. Mikr. Anat. EntwMech. 100:599-638
Strahle U, Jesuthasan S, Blader P, Garcia-Villalba P, Hatta K, Ingham P W. 1997. One eyed pinhead is required for development of the ventral midline of the zebrafish (Danio rerio) neural tube. Genes Funct. 1:131-148
Sumanas S, and Ekker S C. 2001. Xenopus frizzled-7 morphant displays defects in dorsoventral patterning and convergent extension movements during gastrulation. Genesis 30:119-122
Takahashi S, Yokota C, Takano K, Tanegashima K, Onuma Y, Goto J, Asashima M. 2000. Two novel nodal-related genes initiate early inductive events in Xenopus Nieuwkoop center. Development 127:5319-5329
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
Thisse B, Wright C V, Thisse C. 2000. Activin and Nodal-related factors control anteroposterior patterning of the zebrafish embryo. Nature 403:425-428
Thisse C, Thisse B. 1999. Antivin, a novel and divergent member of the TGFbeta superfamily, negatively regulates mesoderm induction. Development 126:229-240
Thomas P, and Beddington R S P. 1996. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6:1487-1496
van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H. 1997. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88:789–799
van de Wetering M, Oosterwegel M, Dooijes D & Clevers H. 1991. Identification and cloning of TCF-1, a T lymphocyte specific transcription factor containing a sequence-specific HMG box. EMBO J. 10:123–132
Vassalli A, Matzuk M M, Gardner H A, Lee K F, Jaenisch R. 1994. Activin/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction. Genes Dev. 8:414-427
Waldrip W R, Bikoff E K, Hoodless P A, Wrana J L, Robertson E J. 1998. Smad2 signaling in extraembryonic tissues determines anteriorposterior polarity of the early mouse embryo. Cell 92:797-808
Watanabe M, and Whitman M. 1999. FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. Development 126:5621-5634
Waxman J S, Hocking A M, Stoick C L, Moon R T. 2004. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated development processes. Development 131:5909-5921 Wegner M. 1999. From head to toes: the multiple facets of Sox proteins. Nucl. Acids Res. 27:1409–1420
Weisberg E, Winnier G E, Chen X, Farnsworth C, Hogan B L M, and Whitman M. 1998. A mouse homologue of FAST-1 transduces TGFβ superfamily signals and is expressed during early embryogenesis. Mech. Dev. 79:17-27
Weng W, Stemple D L.2003. Nodal signaling and vertebrate germ layer formation. Birth Defects Res. 69:325-332
Whitman M. 1998. Smads and early developmental signaling by the TGFβ superfamily. Genes. Dev. 12:2443-2453
Whitman M. 2001. Nodal signaling in early vertebrate embryos: themes and variations. Dev. Cell 1:605-617
Yamada M, Ohkawara B, Ichimura N, Hyodo-Miura J, Urushiyama S, Shirakabe K, Shibuya H. 2003. Negative regulation of wnt signaling by HMG2L1, a novel NLK-binding protein. Genes Cells 8:677-684
Yamamoto M, Meno C, Sakai Y, Shiratori H, Mochida K, Ikawa Y, Saijoh Y, Hamada H. 2001. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev. 15:1242-1256
Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, Meno C, Hamada H. 2003. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130:1795-1804
Yan Y T, Gritsman K, Ding J, Burdine R D, Corrales J D, Price S M, Talbot W S, Schier A F, Shen M M. 1999. Conserved requirement for EGF-CFC genes in vertebrate leftright axis formation. Genes Dev. 13:2527-2537
Yang Z, Liu N, and Lin S. 2001. A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression. Dev. Biol. 231:138-148
Yau T O, Chan C Y, Chan K L, Lee M F, Wong C M, Fan S T, Ng I O. 2005. HDPR1, a novel inhibitor of the Wnt/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 24:1607-1614
Zhang L, Gao X, Wen J, Ning Y, Chen Y G.2006. Dapper1 antagonizes wnt signaling by promoting disheveled degradation. J. Biol. Chem. 281:8607-8612
Zhang L, Zhou H, Su Y, Sun Z, Zhang H, Zhang L, Zhang Y, Ning Y, Chen Y G, Meng A. 2004. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science 306:114-117
Zhou S, Zawel L, Lengauer C, Kinzler K W, and Vogelstein B. 1998. Characterization of human FAST1, a TGF beta and activin signal transducer. Mol. Cell 2:121-127
Zhou X, Sasaki H, Lowe L, Hogan B L, and Kuehn M R. 1993. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature 361:543-547
Agius E, Oelgeschlager M, Wessely O, Kemp C, DeRobertis E M. 2000. Endodermal Nodal-related signals and mesoderm induction in Xenopus. Development 127:1173-1183
Audic Y, Boyle B, Slevin M, and Hartley R S. 2001. Cyclin E morpholino delays embryogenesis in Xenopus. Genesis 30:107-109
Bauer H, Lele Z, Rauch G J, Geisler R, and Hammerschmidt M. 2001. The type I serine/threonine kinase receptor Alk8/Lost-a-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development 128:849-858
Beddington R S. 1994. Induction of a second neural axis by the mouse node. Development 120:613-620
Bell E, Munoz-Sanjuan I, Altmann C R, Vonica A, Brivanlou A H. 2003. Cell fate specification and competence by Coco, a maternal BMP, TGFbeta and Wnt inhibitor. Development 130:1381-1389
Belo J A, Bachiller D, Agius E, Kemp C, Borges A C, et al. 2000. Cerberus-like is a secreted
BMP and nodal antagonist not essential for mouse development. Genesis 26:265-270
Bertocchini F, Stern C D. 2002. The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling. Dev. Cell 3:735-744
Brennan J, Lu C C, Norris D P, Rodriguez T A, Beddington R S, Robertson E J. 2001. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411:965-969
Burdine R D, Schier A F. 2000. Conserved and divergent mechanisms in left-right axis formation. Genes Dev. 14:763-776
Bustin M. 2001. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem. Sci. 26:152-153
Capdevila J, Vogan K J, Tabin C J, Belmonte J C I. 2000. Mechanisms of left-right determination in vertebrates. Cell 101:9-21
Carmany-Rampey A, Schier A F. 2001. Single cell internalization during zebrafish gastrulation. Curr. Biol. 11:1261-1265
Cavallo R A, Cox R T, Moline M M, et al. 1998. Drosophila Tcf and Groucho interact to repress Wingless signalling activity. Nature 395:604–608
Chen H B, Shen J, Ip Y T, Xu L. 2006. Identification of phosphatases for Smad in the BMP/DPP pathway. Genes Dev. 20:648-653
Chen S, Kimelman D. 2000. The role of the yolk syncytial layer in germ layer patterning in zebrafish. Development 127:4681-4689
Chen X, Rubock M J, and Whitman M. 1996. A transcriptional partner for Mad proteins in TGFβ signalling. Nature 383:691-696
Chen Y, Schier A F. 2001. The zebrafish Nodal signal Squint functions as a morphogen. Nature 411:607-610
Chen Y, Schier A F. 2002. Lefty proteins are long-range inhibitors of squint-mediated nodal signaling. Curr. Biol. 12:2124-2128
Cheyette B N, Waxman J S, Miller J R, Takemaru K, Sheldahl L C. 2002. Dapper, a Dishevelled-associated antagonist of beta-catenin and JNK signaling, is required for notochord formation. Dev. Cell 2:449-461
Concha M L, Burdine R D, Russell C, Schier A F, Wilson S W. 2000. A nodal signaling pathway regulates the laterality of neuroanatomical asymmetries in the zebrafish forebrain. Neuron 28:399-409
Conlon F, Lyons K, Takaesu N, Barth K, Kispert A, Hermann B, and Robertson E. 1994. A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 129:1919-1928
Coonrod S A, Bolling L C, Wright P W, Visconti P E, and Herr J C. 2001. A morpholino phenocopy of the mouse MOS mutation. Genesis 30:198-200
Corey D R, Abrams J M. 2001. Morpholino antisense oligonucleotides: tools for investigating vertebrate development. Genome Bio. 2:10151-10153
De Robertis E M, Larrain J, Oelgeschlager M, Wessely O. 2000. The establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nat. Rev. Genet. 1:171-181
Ding J X, Yang L, Yan Y T, Chen A, Desai N, et al. 1998. Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395:702-707
Dougan S T, Warga R M, Kane D A, Schier A F, Talbot W S. 2003. The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm. Development 130:1837–1851
Dunham I, Shimizu N, Roe B A, et al. 1999. The DNA sequence of human chromosome 22. Nature 402:489–495
Erter C E, Solnica-Krezel L, and Wright C V E. 1998. Zebrafish nodal related-2 encodes an early mesendodermal inducer signaling from the extraembryonic yolk syncytial layer. Dev. Biol. 204:361-372
Feldman B, Concha M L, Saude L, Parsons M J, Adams R J, et al. 2002. Lefty antagonism of squint is essential for normal gastrulation. Curr. Biol. 12:2129-2135
Feldman B, Dougan S T, Schier A F, Talbot W S. 2000. Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish. Curr. Biol. 10:5315-5334
Feldman B, Gates M A, Egan E S, Dougan S T, Rennebeck G, et al. 1998. Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature 395:181-185
Feldman B, Gates M A, Egan E S, Dougan S T, Rennebeck G, Sirotkin H I, Rebagliati M R, Toyama R, Haffter P, and Dawid I B. 1998b. Cyclops encodes a nodal-related factor involved in midline signaling. Proc. Natl. Acad. Sci. USA 95:9932-9937
Gaio U, Schweickert A, Fischer A, Garratt A N, Muller T, Ozcelik C, Lankes W, Strehle M, Britsch S, Blum M, Birchmeier C. 1999. A role of the cryptic gene in the correct establishment of the leftright axis. Curr. Biol. 9:1339-1342
Gallego M, and Virshup D M. 2005. Protein serine/threonine phosphatases: life, death, and sleeping. Curr. Opin. Cell Biol. 17:197-202
Gloy J, Hikasa H, Sokol S Y. 2002. Frodo interacts with Dishevelled to transducer Wnt signals. Nat. Cell Biol. 4:351-357
Gray P C, Harrison C A, Vale W. 2003. Cripto forms a complex with activin and type II activin receptors and can block activin signaling. Proc. Natl. Acad. Sci. USA 100:193-198
Green J. 2002. Morphogen gradients, positional information, and Xenopus: interplay of theory and experiment. Dev. Dyn. 225:392-408
Green J B, Smith J C. 1990. Graded changes in dose of a Xenopus activin A homologue elicit stepwise transitions in embryonic cell fate. Nature 347:391-394
Gritsman K, Talbot W S, Schier A F. 2000. Nodal signaling patterns the organizer. Development 127:921-932
Gritsman K, Zhang J, Cheng S, Heckscher E, Talbot W S, Schier A F. 1999. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell 97:121-132
Gurdon JB, Bourillot P Y. 2001. Morphogen gradient interpretation. Nature 413:797-803
Gurdon J B, Harger P, Mitchell A, Lemaire P. 1994. Activin signaling and response to a morphogen gradient. Nature 371:487-492
Gu Z Y, Nomura M, Simpson B B, Lei H, Feijen A, van den Rijnden-van Raaij J, Donahoe P K, and Li E. 1998. The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev. 12:844-857
Hamada H, Meno C, Watanabe D, Saijoh Y. 2002. Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet. 3:103-113
Harland R, Gerhart J. 1997. Formation and function of Spemann’s organizer. Annu. Rev. Cell Dev. Biol. 13:611-667.
Hatta K, Kimmel C B, Ho R K, Walker C. 1991. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350:339-341
Heasman J, Kofron M, and Wylie C. 2000. Beta-catenin signaling activity dissected in the early Xenopus embryo: A novel antisense approach. Dev. Biol. 222:124-134
Hill C. 2001. TGFβ signaling pathways in early Xenopus development. Curr. Opin. Genet. Dev. 11:533-540
Hoodless P A, Pye M, Chazaud C, Labbe E, Attisano L, Rossant J, Wrana J L. 2001. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15:1257-1271
Howard E W, Newman L A, Oleksyn D W, Angerer R C, and Angerer L M. 2001. SpKrl: A direct target of beta-catenin regulation required for endoderm differentiation in sea urchin embryos. Development 128:365-375
Huang H C, Murtaugh L C, Vize P D, and Whitman M. 1995. Identification of a potential regulator of early transcriptional responses to mesoderm inducers in the frog embryo. EMBO J. 14:5965-5973
Jones C M, Kuehn M R, Hogan B L, Smith J C, Wright C V. 1995. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121:3651-3662
Joseph E M, Melton D A. 1997. Xnr4: a Xenopus nodal-related gene expressed in the Spemann organizer. Dev Biol 184:367-372
Katoh M, Katoh M. 2003. Identification and characterization of human DAPPER1 and DAPPER2 genes in silico. Int. J. Oncol. 22:907-913
Katoh M, Katoh M. 2005. Identification and characterization of rat Dact1 and Dact2 genes in silico. Int. J. Mol. Med. 15:1045-1049
Kidder G M. 1992. The genetic program for preimplantation development. Dev. Genet. 13:319-325
Kimmel C B, Ballard W W, Kimmel S R, Ullmann B, and Schilling T F. 1995. Stages of embryonic development of the zebrafish. Dev. Dyn. 203:253-310
Kos R, Reedy M V, Johnson R L, and Erickson C A. 2001. The winged-helix transcription factor FoxD3 is important for establishing the neural crest lineage and repressing melanogenesis in avian embryos. Development 128:1467-1479
Labbe′ E, Silvestri C, Hoodless P A, Wrana J L, and Attisano L. 1998. Smad2 and Smad3 positively and negatively regulate TGFbeta-dependent transcription through the forkhead DNA-binding protein FAST2. Mol. Cell 2:109-120
Lee K J, Mendelsohn M, Jessell T M. 1998. Neuronal patterning by BMPs: a requirement for GDF7 in the generation of a discrete class of commissural interneurons in the mouse spinal cord. Genes Dev. 12:3394-3407
Levanon D, Goldstein R E, Bernstein Y, Tang H, Goldenberg D, Stifani S, Paroush Z, Groner Y. 1998. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl. Acad. Sci. USA 95:11590–11595
Lin X, Duan X, Liang Y, Su Y, Wrighton K H, Long J, Hu M, Davis C M, Wang J, Brunicardi F C, Shi Y G, Chen Y G, Meng A, Feng X H. 2006. PPM1A functions as a Smad phosphatase to terminate TGFβ signaling. Cell Scheduled publishing date: June 2nd issue
Long S, Ahmad N, Rebagliati M. 2003. The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development 130:2303-2316
Lou R, An M, Arduini B L, Henion P D. 2001. Specific pan-neural crest expression of zebrafish crestin throughout embryonic development. Dev. Dyn. 220:169-174
Lowe L A,Yamada S, Kuehn M R. 2001. Genetic dissection of nodal function in patterning the mouse embryo. Development 128:1831-1843
Lu C C, Brennan J, Robertson E J. 2001. From fertilization to gastrulation: axis formation in the mouse embryo. Curr. Opin. Genet. Dev. 11:384-392
Manzanares M, and Krumlauf R. 2000. Raising the roof. Nature 403:720-721
Massague′ J. 1998. TGFβ Signal Transduction. Annu. Rev. Biochem. 67:753-791
Massague′ J, and Wotton D. 2000. Transcriptional control by the TGF/Smad signaling system. EMBO J. 19:1745-1754
Meno C, Gritsman K, Ohishi S, Ohfuji Y, Heckscher E, Mochida K, Shimono A, Kondoh H, Talbot W S, Robertson E J, Schier A F, Hamada H. 1999. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4:287-298
Meno C, Saijoh, Y, Fujii H, Ikeda M, Yokoyama T, Yokoyama M, Toyoda Y, Hamada H. 1996. Left-right asymmetric expression of the TGF beta-family member lefty in mouse embryos. Nature 381:151-155
Meno C, Takeuchi J, Sakuma R, Koshiba-Takeuchi K, Ohishi S, Saijoh Y, Miyazaki J, ten Dijke P, Ogura T, Hamada H. 2001. Diffusion of nodal signaling activity in the absence of the feedback inhibitor Lefty2. Dev. Cell 1:127-138
Mercola M, Levin M. 2001. Left-right asymmetry determination in vertebrates. Annu. Rev. Cell Dev. Biol. 17:779-805
Montero J, and Heisenberg C. 2004. Gastrulation dynamics: cells move into focus. Trends in Cell Bio. 14:620-627
Nasevicius A, and Ekker S C. 2000. Effective targeted gene “knockdown” in zebrafish. Nat. Genet. 26:216-220
Nieuwkoop P D. 1973. The organization center of the amphibian embryo: its origin, spatial organization, and morphogenetic action. Adv. Morphog. 10:1–39
Norris D P, Brennan J, Bikoff E K, Robertson E J. 2002. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129:3455-3468
Oh S P, and Li E. 1997. The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse. Genes Dev. 11:1812-1826
Perea-Gomez A, Vella F D, Shawlot W, Oulad-Abdelghani M, Chazaud C, Meno C, Pfister V, Chen L, Robertson E, Hamada H, Behringer R R, Ang S L. 2002. Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks. Dev. Cell 3:745-756
Pevny L H & Lovell-Badge R. 1997. Sox genes find their feet. Curr. Opin. Genet. Dev. 7:338–344
Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis E M. 1999. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397:707-710
Pogoda H M, Solnica-Krezel L, Driever W, and Meyer D. 2000. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of Nodal signaling required for organizer formation. Curr. Biol. 10:1041-1049
Reissmann E, Jornvall H, Blokzijl A, Andersson O, Chang C, Minchiotti G, Persico M G, Ibanez C F, and Brivanlou A H. 2001. The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development. Genes Dev. 15:2010-2022
Renucci A, Lemarchandel V, and Rosa F. 1996. An activated form of type I serine/threonine kinase receptor TARAM-A reveals a specific signalling pathway involved in fish head organizer formation. Development 122:3735-3743
Roose J, Molenaar M, Peterson J, Hurenkamp J, Brantjes H, Moerer P, van de Wetering M, Destree O, Clevers H. 1998. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395:608–612
Ross J J, Shimmi O, Vilmos P, Petryk A, Kim H, Gaudenz K, Hermanson S, Ekker S C, O’Connor M B, and Marsh J L. 2001. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 410:479-483
Saijoh Y, Adachi H, Sakuma R, Yeo C Y, Yashiro K, Watanabe M, Hashiguchi H, Mochida K, Ohishi S, Kawabata M, Miyazono K, Whitman M, Hamada H. 2000. Left-right asymmetric expression of lefty2 and nodal is induced by a signaling pathway that includes the transcription factor FAST2. Mol. Cell 5:35-47
Sampath K, Rubinstein A L, Cheng A M, Liang J O, Fekany K, Solnica-Krezel L, Korzh V, Halpern M E, and Wright C V. 1998. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395:185-189
Satou Y, Imai K S, and Satoh N. 2001. Action of morpholinos in Ciona embryos. Genesis 30:103-106
Schier A F. 2001. Axis formation and patterning in zebrafish. Current Opinion in Genetics & Development 11:393-404
Schier A F. 2003. Nodal signaling in vertebrate development. Annu. Rev. Cell Dev. Biol. 19:589-621
Schier A F, Neuhauss S C, Helde K A, Talbot W S, Driever W. 1997. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124:327-342
Schier A F, Shen M M. 2000. Nodal signaling in vertebrate development. Nature 403:385-389
Schier A F, and Talbot W S. 1998. Zebrafish organizer development and germ-layer formation require nodal- related signals. Nature 395:181-185
Schier A F, and Talbot W S. 2001. Nodal signaling and the zebrafish organizer. Int. J. Dev. Biol. 45:289-297
Schultz R M. 1986. Molecular aspects of mammalian oocyte growth and maturation. In Experimental approaches to mammaliam embryonic development. 195-237. Cambridge University Press, England.
Schweickert A, Deissler K, Blum M, and Steinbeisser H. 2001. Pitx1 and Pitx2c are required for ectopic cement gland formation in Xenopus laevis. Genesis 30:144-148
Segawa H, Miyashita T, Hirate Y, Higashijima S, Chino N, Uyemura K, Kikuchi Y, and Okamoto H. 2001. Functional repression of Islet-2 by disruption of complex with Ldb impairs peripheral axonal outgrowth in embryonic zebrafish. Neuron 30:423-436
Seroussi E, Kedra D, Kost-Alimova M, Sandberg-Nordqvist A C, Fransson I, Jacobs J F, Fu Y, Pan H Q, Roe B A, Imreh S, Dumanski J P. 1999. TOM1 genes map to human chromosome 22q13.1 and mouse chromosome 8C1 and encode proteins similar to the endosomal proteins HGS and STAM. Genomics 57:380-388
Shen M M, and Schier A F. 2000. The EGF-CFC gene family in vertebrate development. Trends Genet. 16:303-309
Shepherd I T, Beattie C E, and Raible D W.2001. Functional analysis of zebrafish GDNF. Dev. Biol. 231:420-435
Sirotkin H I, Gates M A, Kelly P D, Schier A F, and Talbot W S. 2000. Fast1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol. 10:1051-1054
Smith J C. 1995. Mesoderm-inducing factors and mesodermal patterning. Curr. Opin. Cell Biol. 7:856-861
Song J, Oh S P, Schrewe H, Nomura M, Lei H, Okano M, Gridley T, and Li E. 1999. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 213:157-169
Spemann H, and Mangold H. 1924. Uber Induktion von Embryo-nanlagen durch Implantation artfremder Organisatoren. Arch. Mikr. Anat. EntwMech. 100:599-638
Strahle U, Jesuthasan S, Blader P, Garcia-Villalba P, Hatta K, Ingham P W. 1997. One eyed pinhead is required for development of the ventral midline of the zebrafish (Danio rerio) neural tube. Genes Funct. 1:131-148
Sumanas S, and Ekker S C. 2001. Xenopus frizzled-7 morphant displays defects in dorsoventral patterning and convergent extension movements during gastrulation. Genesis 30:119-122
Takahashi S, Yokota C, Takano K, Tanegashima K, Onuma Y, Goto J, Asashima M. 2000. Two novel nodal-related genes initiate early inductive events in Xenopus Nieuwkoop center. Development 127:5319-5329
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
Thisse B, Wright C V, Thisse C. 2000. Activin and Nodal-related factors control anteroposterior patterning of the zebrafish embryo. Nature 403:425-428
Thisse C, Thisse B. 1999. Antivin, a novel and divergent member of the TGFbeta superfamily, negatively regulates mesoderm induction. Development 126:229-240
Thomas P, and Beddington R S P. 1996. Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Curr. Biol. 6:1487-1496
van de Wetering M, Cavallo R, Dooijes D, van Beest M, van Es J, Loureiro J, Ypma A, Hursh D, Jones T, Bejsovec A, Peifer M, Mortin M, Clevers H. 1997. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88:789–799
van de Wetering M, Oosterwegel M, Dooijes D & Clevers H. 1991. Identification and cloning of TCF-1, a T lymphocyte specific transcription factor containing a sequence-specific HMG box. EMBO J. 10:123–132
Vassalli A, Matzuk M M, Gardner H A, Lee K F, Jaenisch R. 1994. Activin/inhibin beta B subunit gene disruption leads to defects in eyelid development and female reproduction. Genes Dev. 8:414-427
Waldrip W R, Bikoff E K, Hoodless P A, Wrana J L, Robertson E J. 1998. Smad2 signaling in extraembryonic tissues determines anteriorposterior polarity of the early mouse embryo. Cell 92:797-808
Watanabe M, and Whitman M. 1999. FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. Development 126:5621-5634
Waxman J S, Hocking A M, Stoick C L, Moon R T. 2004. Zebrafish Dapper1 and Dapper2 play distinct roles in Wnt-mediated development processes. Development 131:5909-5921 Wegner M. 1999. From head to toes: the multiple facets of Sox proteins. Nucl. Acids Res. 27:1409–1420
Weisberg E, Winnier G E, Chen X, Farnsworth C, Hogan B L M, and Whitman M. 1998. A mouse homologue of FAST-1 transduces TGFβ superfamily signals and is expressed during early embryogenesis. Mech. Dev. 79:17-27
Weng W, Stemple D L.2003. Nodal signaling and vertebrate germ layer formation. Birth Defects Res. 69:325-332
Whitman M. 1998. Smads and early developmental signaling by the TGFβ superfamily. Genes. Dev. 12:2443-2453
Whitman M. 2001. Nodal signaling in early vertebrate embryos: themes and variations. Dev. Cell 1:605-617
Yamada M, Ohkawara B, Ichimura N, Hyodo-Miura J, Urushiyama S, Shirakabe K, Shibuya H. 2003. Negative regulation of wnt signaling by HMG2L1, a novel NLK-binding protein. Genes Cells 8:677-684
Yamamoto M, Meno C, Sakai Y, Shiratori H, Mochida K, Ikawa Y, Saijoh Y, Hamada H. 2001. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev. 15:1242-1256
Yamamoto M, Mine N, Mochida K, Sakai Y, Saijoh Y, Meno C, Hamada H. 2003. Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130:1795-1804
Yan Y T, Gritsman K, Ding J, Burdine R D, Corrales J D, Price S M, Talbot W S, Schier A F, Shen M M. 1999. Conserved requirement for EGF-CFC genes in vertebrate leftright axis formation. Genes Dev. 13:2527-2537
Yang Z, Liu N, and Lin S. 2001. A zebrafish forebrain-specific zinc finger gene can induce ectopic dlx2 and dlx6 expression. Dev. Biol. 231:138-148
Yau T O, Chan C Y, Chan K L, Lee M F, Wong C M, Fan S T, Ng I O. 2005. HDPR1, a novel inhibitor of the Wnt/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene 24:1607-1614
Zhang L, Gao X, Wen J, Ning Y, Chen Y G.2006. Dapper1 antagonizes wnt signaling by promoting disheveled degradation. J. Biol. Chem. 281:8607-8612
Zhang L, Zhou H, Su Y, Sun Z, Zhang H, Zhang L, Zhang Y, Ning Y, Chen Y G, Meng A. 2004. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science 306:114-117
Zhou S, Zawel L, Lengauer C, Kinzler K W, and Vogelstein B. 1998. Characterization of human FAST1, a TGF beta and activin signal transducer. Mol. Cell 2:121-127
Zhou X, Sasaki H, Lowe L, Hogan B L, and Kuehn M R. 1993. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature 361:543-547