Developmental biology: microRNAs create major divisions in embryogenesis

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During vertebrate development, asymmetrical Wnt signaling regulates the distribution of microRNAs miR-15 and miR-16, which in turn downregulate the activin A receptor to establish a Nodal signaling gradient.

One of the earliest and most important stages in vertebrate development — the creation of the organizing centre — could be determined by the action of two microRNAs (miRNAs). This is the first report of miRNAs — which are best known for their effects on gene expression — being involved in cell-lineage decisions, and could be just one example of these molecules having essential functions in embryonic patterning.

Spemann's organizer has been the subject of intense scrutiny since the discovery, almost 100 years ago, that this portion of the vertebrate embryo kick-starts the patterning of all the rest. The position of the organizer is initially determined by asymmetrical WNT signalling; this somehow sets up a gradient of Nodal signalling that is strongest in the dorsal portion of the embryo, where the organizer will form. A team led by Stefano Piccolo finds that two miRNAs lie at the intersection of these two signalling pathways, to ensure that Nodal signalling is restricted to the dorsal region of the embryo.

The authors identified the two miRNAs in an experiment designed to test whether miRNAs extracted from frog gastrulas could reduce Nodal signalling when reinjected at the two-cell stage. Two miRNAs, miR-15 and miR-16, had this effect: they act not on Nodal itself but specifically on the mRNA of a Nodal receptor, Acvr2a.

What are the developmental consequences of this interaction, which is conserved from amphibians to humans? When early-stage embryos were injected with miR-15, markers of Nodal signalling (such as chordin expression) were downregulated, as you would expect, by antagonizing Acvr2a function. Injection into older embryos impaired the formation of dorsal structures, which depends on high levels of Nodal. In contrast to these miRNA overexpression phenotypes, which had the effect of reducing organizer function, loss of the miRNAs caused an expansion of the organizer tissue, in a manner that was dependent on Nodal signalling.

If Nodal signalling is expanded when the two miRNAs are missing, then there is a possibility that miRNAs reside in the ventral portion of the embryo, where they prevent Nodal responsiveness in this region. This was the case: the expression pattern of mature miR-15 and miR-16 was enriched in the ventral portion of the embryo, in a complementary pattern to that of Acvr2a. Such a set up would restrict Nodal signalling, and thus the organizer, to the dorsal-most region of the embryo.

The authors also show that Wnt regulates the distribution of miR-15 and miR-16 — probably directly through beta -catenin. This suggests that the miRNAs act at the crossroads of two growth factor signalling pathways by translating one gradient into the other.

The study raises the hope that the principles underlying the interaction between miR-15 and Acvr2a in Xenopus laevis will also apply to other developmental situations — that miRNAs are required not only to maintain established cell fates but also to break symmetry in the early embryo.

Tanita Casci

References

Martello, G. et al. MicroRNA control of Nodal signalling. Nature 449, 183–188 (2007) | Article | PubMed |