The vertebrate body plan is established during gastrulation, when cells move inwards to form the mesodermal and endodermal germ layers. Signals from a region of dorsal mesoderm, which is termed the organizer, pattern the body axis by specifying the fates of neighbouring cells1,2. The organizer is itself induced by earlier signals1. Although members of the transforming growth factor-β (TGF-β) and Wnt families have been implicated in the formation of the organizer, no endogenous signalling molecule is known to be required for this process1. Here we report that the zebrafish squint (sqt)3 and cyclops (cyc)4 genes have essential, although partly redundant, functions in organizer development and also in the formation of mesoderm and endoderm. We show that the sqt gene encodes a member of the TGF-β superfamily that is related to mouse nodal. cyc encodes another nodal-related protein5,6, which is consistent with our genetic evidence that sqt and cyc have overlapping functions. The sqt gene is expressed in a dorsal region of the blastula that includes the extraembryonic yolk syncytial layer (YSL). The YSL has been implicated as a source of signals that induce organizer development and mesendoderm formation2,7. Misexpression of sqt RNA within the embryo or specifically in the YSL induces expanded or ectopic dorsal mesoderm. These results establish an essential role for nodal-related signals in organizer development and mesendoderm formation.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Harland, R. & Gerhart, J. Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Biol. 13, 611–667 (1997).
Schier, A. F. & Talbot, W. S. The zebrafish organizer. Curr. Opin. Genet. Dev. 8, 464–471 (1998).
Heisenberg, C. P. & Nüsslein-Volhard, C. The function of silberblick in the positioning of the eye anlage in the zebrafish embryo. Dev. Biol. 184, 85–94 (1997).
Hatta, K., Kimmel, C. B., Ho, R. K. & Walker, C. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature 350, 339–341 (1991).
Sampath, K.et al. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature(in the press).
Rebagliati, M. R., Toyama, R., Haffter, P. & Dawid, I. B. Cyclops encodes a nodal-related factor involved in midline signalling. Proc. Natl Acad. Sci. USA 95, 9932–9937 (1998).
Mizuno, T., Yamaha, E., Wakahara, M., Kuroiwa, A. & Takeda, H. Mesoderm induction in zebrafish. Nature 383, 131–132 (1996).
Thisse, C., Thisse, B., Halpern, M. E. & Postlethwait, J. H. goosecoid expression in neurectoderm and mesendoderm is disrupted in zebrafish cyclops gastrulas. Dev. Biol. 164, 420–429 (1994).
Stachel, S. E., Grunwald, D. J. & Myers, P. Z. Lithium perturbation and goosecoid expression identify a dorsal specification pathway in the pregastrula zebrafish. Development 117, 1261–1274 (1993).
Schulte-Merker, S., Ho, R. K., Herrmann, B. G. & Nüsslein-Volhard, C. The protein product of the zebrafish homologue of the mouse T gene is expressed in nuclei of the germ ring and the notochord of the early embryo. Development 116, 1021–1032 (1992).
Strähle, U., Blader, P., Henrique, D. & Ingham, P. W. Axial, a zebrafish gene expressed along the developing body axis, shows altered expression in cyclops mutant embryos. Genes Dev. 7, 1436–1446 (1993).
Schier, A. F., Neuhauss, S. C. F., Helde, K. A., Talbot, W. S. & Driever, W. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development 124, 327–342 (1997).
Thisse, C., Thisse, B., Schilling, T. F. & Postlethwait, J. H. Structure of the zebrafish snail1 gene and its expression in wild-type, spadetail and no tail mutant embryos. Development 119, 1203–1215 (1993).
Kimmel, C. B., Ballard, W. W., Kimmel, S. R., Ullmann, B. & Schilling, T. F. Stages of embryonic development of the zebrafish. Dev. Dyn. 203, 253–310 (1995).
Krauss, S., Johansen, T., Korzh, V. & Fjose, A. Expression of the zebrafish paired box gene pax [ zf-b ] during early neurogenesis. Development 113, 1193–1206 (1991).
Rebagliati, M. R., Toyama, R., Fricke, C., Haffter, P. & Dawid, I. B. Zebrafish nodal-related genes are implicated in axial patterning and establishing left-right asymmetry. Dev. Biol. 199, 261–272 (1998).
Zhou, X., Sasaki, H., Lowe, L., Hogan, B. L. & Kuehn, M. R. Nodal is a novel TGF-β-like gene expressed in the mouse node during gastrulation. Nature 361, 543–547 (1993).
Jones, C. M., Kuehn, M. R., Hogan, B. M. L., Smith, J. C. & Wright, C. V. E. Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation. Development 121, 3651–3662 (1995).
Toyama, R., O'Connell, M. L., Wright, C. V. E., Kuehn, M. R. & Dawid, I. B. Nodal induces ectopic goosecoid and lim1 expression and axis duplication in zebrafish. Development 121, 383–391 (1995).
Conlon, F. L.et al. Aprimary requirement for nodal in the formation and maintenance of the primitive steak in the mouse. Development 120, 1919–1928 (1994).
Matzuk, M. M.et al. Functional analysis of activins during mammalian development. Nature 374, 354–356 (1995).
Kanki, J. P. & Ho, R. K. The development of the posterior body in zebrafish. Development 124, 881–893 (1997).
Schneider, S., Steinbeisser, H., Warga, R. M. & Hausen, P. β-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech. Dev. 57, 191–198 (1996).
Talbot, W. S.et al. Genetic analysis of chromosomal rearrangements in the cyclops region of the zebrafish genome. Genetics 148, 373–380 (1998).
Schier, A. F.et al. Mutations affecting the development of the embryonic zebrafish brain. Development 123, 165–178 (1996).
Postlethwait, J. H.et al. Vertebrate genome evolution and the zebrafish gene map. Nature Genet. 18, 345–349 (1998).
Knapik, E. W.et al. Amicrosatellite genetic linkage map for zebrafish (Danio rerio). Nature Genet. 18, 338–343 (1998).
Smith, W. C., McKendry, R., Ribisi, S. & Harland, R. M. Anodal-related gene defines a physical and functional domain within the Spemann organizer. Cell 82, 37–46 (1995).
Joseph, E. M. & Melton, D. A. Xnr4 : a Xenopus nodal -related gene expressed in the Spemann organizer. Dev. Biol. 184, 367–372 (1997).
We thank C. Erter, C. Wright, M. Rebagliati and I. Dawid for sharing and allowing us to cite their unpublished data; members of the Talbot and Schier laboratories for discussions; T. Lepage, D.Kimelman and C.-P. Heisenberg for reagents and fish stocks; S. McManus for fish care; and A. Ruiz i Altaba and G. Fishell for comments on the manuscript. We acknowledge postdoctoral fellowship support from the NIH (B.F. and H.I.S.) and ACS (S.T.D.). This work was supported by grants from the NIH (W.S.T. and A.F.S.) and an NYU Whitehead Fellowship (W.S.T.).
About this article
Developmental Biology (2019)
Evolution of nodal and nodal-related genes and the putative composition of the heterodimers that trigger the nodal pathway in vertebrates
Evolution & Development (2019)
Cold Spring Harbor Perspectives in Biology (2018)
Reduced expression of the Nodal co-receptor Oep causes loss of mesendodermal competence in zebrafish