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The establishment of spemann's organizer and patterning of the vertebrate embryo

Abstract

Molecular studies have begun to unravel the sequential cell–cell signalling events that establish the dorsal–ventral, or 'back-to-belly', axis of vertebrate animals. In Xenopus and zebrafish, these events start with the movement of membrane vesicles associated with dorsal determinants. This mediates the induction of mesoderm by generating gradients of growth factors. Dorsal mesoderm then becomes a signalling centre, the Spemann's organizer, which secretes several antagonists of growth-factor signalling. Recent studies have led to new models for the regulation of cell–cell signalling during development, which may also apply to the homeostasis of adult tissues.

Key Points

  • Dorso-ventral asymmetry in the fertilized Xenopus egg starts when a set of parallel cortical microtubules transport small membrane vesicles, which bind Dishevelled protein on their cytoplasmic side, towards the dorsal aspect of the fertilized egg.

  • Transport of these cytoplasmic determinants is required for the differentiation of neural tissue, notochord, somite and kidney.

  • The inhibition of β-Catenin degradation in the dorsal side is the first step in a biochemical cascade that leads to dorsal development.

  • At the blastula stage, a gradient of Nodal-related TGF-β factors (Xnrs) is formed in the endoderm, which induces both ventral and dorsal mesoderm. High Xnr levels lead to the induction of Spemann's organizer tissue in the overlying dorsal mesoderm.

  • The organizer secretes a cocktail of growth factor antagonists such as Noggin, Chordin, Cerberus, Frzb-1 and Dkk-1, which further refine the pattern.

  • Chordin binds bone morphogenetic proteins (BMPs) through cysteine-rich modules, designated CRs. The inhibition of BMP by Chordin can be reversed by the combined action of Xolloid, a zinc metalloprotease, and Twisted-gastrulation (xTsg).

  • xTsg is a BMP-binding molecule that can form ternary complexes with full-length Chordin and BMP, thereby converting full-length Chordin into an even better BMP antagonist.

  • After Chordin is cleaved by Xolloid, xTsg displaces the binding of BMP to CRs, thereby promoting, rather than preventing, signalling through BMP receptors.

  • Many extracellular proteins contain CR domains of the Chordin type, raising the possibility that the studies in embryos may provide a general model for the fine regulation of signalling by growth factors in the extracellular space.

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Figure 1: The anatomy of Xenopus development.
Figure 2: The ultraviolet (UV) phenotype of irradiated embryos can be rescued by many different molecules.
Figure 3: Dorsal determinants and the transport of membrane vesicles to the dorsal side.
Figure 4: Two-step model of mesoderm induction in Xenopus.
Figure 5: Spemann's organizer is a source of secreted growth factor antagonists.
Figure 6: Genetics of chordin/sog in zebrafish and Drosophila.
Figure 7: A molecular pathway involving Chordin, Xolloid and Twisted-gastrulation regulates the dorsal–ventral activity gradient of bone morphogenetic protein in Xenopus.

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Acknowledgements

We apologize to the many colleagues whose work we were unable to discuss owing to space limitations. We thank J. Abreu, J.I. Kim and E. Pera for comments on the manuscript. J.L. is a PEW Latin American Fellow, and M.O. and O.W. are Human Frontiers Science Program Organization postdoctoral fellows. Our laboratory is supported by the NIH and the Howard Hughes Medical Institute.

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Authors

Supplementary information

Related links

Related links

DATABASE LINKS

β-Catenin

Nodal

Noggin

Chordin

Cerberus

Frzb-1

Crescent

Dickkopf

Xolloid

Twisted-gastrulation

Dishevelled

Frizzled-7 Wnt receptor

siamois

Xtwin

Nodal-related-3

Axin

Cyclops

Squint

Goosecoid

Vg1

BMP-4

Derrière

Smad2

VegT

Dlx-3

BMP-2

zebrafish Goosecoid

Mixer

Smad4

FAST-1

XIHbox-8

Xnr-1

Xnr-2

Xnr-4

Follistatin

Vent

Vox

sFRP-2

Sizzled

Xwnt-8

lefty-2

nodal

BMP-2b

Smad5

BMP-7

short-gastrulation

Dpp

screw

Drosophila Tolloid

zebrafish tolloid

Dtsg

GBB

procollagen I

N-terminal proteinase

procollagen II

procollagen V

CTGF

Thrombospondin-1

Crossveinless-2

Kielin

APC

GSK-3

FURTHER INFORMATION

Xenbase

The zebrafish information network

Axeldb

De Robertis lab homepage

ENCYCLOPEDIA OF LIFE SCIENCES

Xenopus embryo: β-Catenin and dorso–ventral axis formation

BMP antagonists and neural induction

Glossary

DORSAL CRESCENT

Region of reduced pigmentation that marks the future dorsal side of the fertilized egg.

BONE MORPHOGENETIC PROTEINS

(BMPs). Molecules of the TGF-β family that can induce bone formation and ventralize the vertebrate embryo. In zebrafish, a mutation in either BMP-2b or BMP-7 has a similar effect, suggesting that they work as heterodimers; either mutation also inhibits transcription of BMP-4.

HYPOCHORD

Transient rod-like structure derived from the endoderm, which is located beneath the notochord in vertebrate embryos.

SYNEXPRESSION GROUP

A group of genes that have similar expression domains in the embryo, which usually correlate with function in a common biochemical pathway.

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De Robertis, E., Larraín, J., Oelgeschläger, M. et al. The establishment of spemann's organizer and patterning of the vertebrate embryo. Nat Rev Genet 1, 171–181 (2000). https://doi.org/10.1038/35042039

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