Nodal morphogens - PubMed (original) (raw)

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Nodal morphogens

Alexander F Schier. Cold Spring Harb Perspect Biol. 2009 Nov.

Abstract

Nodal signals belong to the TGF-beta superfamily and are essential for the induction of mesoderm and endoderm and the determination of the left-right axis. Nodal signals can act as morphogens-they have concentration-dependent effects and can act at a distance from their source of production. Nodal and its feedback inhibitor Lefty form an activator/inhibitor pair that behaves similarly to postulated reaction-diffusion models of tissue patterning. Nodal morphogen activity is also regulated by microRNAs, convertases, TGF-beta signals, coreceptors, and trafficking factors. This article describes how Nodal morphogens pattern embryonic fields and discusses how Nodal morphogen signaling is modulated.

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Figures

Figure 1.

Figure 1.

The Nodal signaling pathway. After processing of the Nodal precursor by convertases, Nodal ligands signal through activin receptors and EGF-CFC coreceptors. Cerberus and Lefty act as extracellular inhibitors. MicroRNAs belonging to the miR-430 family target Nodal (zebrafish squint) and Lefty mRNAs for degradation and repression. Mir-15/16 represses the type II activin receptor. Rap2 is involved in the recycling of activin receptors whereas Dapper 2 targets activin receptor complexes for degradation in the lysosome. Pathway activation is mediated by phosphorylation of Smad2 and its association with Smad4 and transcription factors such as FoxH1, Mixer, and p53. Phospho-Smad2 is dephosphorylated by PPM1A and exported from the nucleus by RanBP3. Smad4 activity and stability is regulated by the ubiquitinase Ectodermin and the deubiquitinase FAM/Usp9x. See text for details.

Figure 2.

Figure 2.

Mesoderm and endoderm induction in zebrafish. Ectoderm, mesoderm, and mesendoderm precursors are arranged from animal to vegetal positions at the blastula stage. The Nodal signals Squint and Cyclops and the inhibitor Lefty are expressed at the blastula margin. Genetic studies suggest that Cyclops has short-range activity whereas Squint and Lefty have long-range activity. See text for details.

Figure 3.

Figure 3.

Model for left–right patterning by Nodal and Lefty. Nodal/GDF1 heterodimers form in the region of the node and activate Nodal signaling in the lateral plate mesoderm (LPM). Cilia-induced fluid flow biases Nodal activation toward the left. Subsequent Nodal autoregulation, induction of Lefty expression, and long-range inhibition by Lefty lead to robust pathway activation on the left and inhibition on the right. See text for details.

Figure 4.

Figure 4.

Reaction/Diffusion Model for Patterning by Nodal and Lefty. Nodal induces its own expression and forms a concentration gradient (c, concentrations of Nodal and Lefty; x, distance). Lefty is induced by Nodal and blocks Nodal signaling. The model postulates that Lefty has a longer range and more shallow distribution than Nodal. Thus, Nodal signaling is active close to the source but inhibited at a distance. See text for details.

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References

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