Developmental genetics: Wizard of clocks

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Wnt signaling has a key role in the clock that controls vertebrate segmentation.

Finding out exactly what is pulling the levers that control the vertebrate segmentation clock has turned out to be as surprising as it was for Dorothy when she pulled back the curtain to reveal the real Wizard of Oz. Alexander Aulehla and colleagues in their new study, published in Developmental Cell, show that Wnt3a has a key role in the clock that controls segmentation.

It is only recently that molecular evidence has emerged to show that a segmentation clock and a molecular gradient in the presomitic mesoderm (PSM) are involved in formation of the precursors to vertebrae — the somites. The next step was to find genes the expression of which oscillates in a clocklike fashion and which have a graded expression pattern in the PSM.

Using in situ hybridization screening on whole-mount mouse embryos, Aulehla et al. identified a completely unexpected candidate that meets these criteria — Axin2, a negative regulator in the Wnt/ beta -catenin signalling cascade. This first link between the Wnt/ beta -catenin pathway and the segmentation process is a neat result in itself, but the authors went on to show that Axin2 is unique in that it cycles out of phase from the other cycling genes and, unlike them, continues to cycle even when Notch signalling is impaired.

So, if it is not Notch signalling, what is controlling Axin2 expression? With a reporter-gene assay that shows that a dominant active form of beta -catenin strongly activates the Axin2 promoter, the authors provide convincing evidence that Axin2 is under the direct control of Wnt/ beta -catenin signalling. An in vivo reporter assay showed that mutating Lef/Tcf binding sites abolished the characteristic Axin2-like expression pattern of the reporter gene in structures derived from the PSM.

However, Aulehla and colleagues really start to pull that curtain back by showing that in embryos with reduced expression of Wnt3a, Axin2 is strongly downregulated in the tailbud and PSM, as is Lfng, which is a cycling gene that is a direct target of Notch signalling. Coupled with further in vivo data that show the importance of Wnt3a in somitogenesis, these results downgrade Notch signalling to an intermediate link in the chain and show that Wnt3a, through Axin2, is probably pulling the levers.

The authors present a plausible model for the segmentation process based on Wnt signalling that can explain the segmentation clock and the PSM gradient. Their model will, of course, need testing, but at least now we know to focus on Wnt3a, the little guy behind the curtain, rather than the booming voice of Notch signalling.

Nick Campbell

References

Aulehla, A. et al. Wnt3a plays a major role in the segmentation clock controlling somitogenesis. Dev. Cell 4, 395–406 (2003) | PubMed |
Saga, Y. & Takeda, H. The making of the somite: molecular events in vertebrate segmentation Nature Rev. Genet. 2, 835–845 (2001) | Article | PubMed |

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