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MicroRNA control of Nodal signalling

Abstract

MicroRNAs are crucial modulators of gene expression, yet their involvement as effectors of growth factor signalling is largely unknown. Ligands of the transforming growth factor-β superfamily are essential for development and adult tissue homeostasis. In early Xenopus embryos, signalling by the transforming growth factor-β ligand Nodal is crucial for the dorsal induction of the Spemann’s organizer. Here we report that Xenopus laevis microRNAs miR-15 and miR-16 restrict the size of the organizer by targeting the Nodal type II receptor Acvr2a. Endogenous miR-15 and miR-16 are ventrally enriched as they are negatively regulated by the dorsal Wnt/β-catenin pathway. These findings exemplify the relevance of microRNAs as regulators of early embryonic patterning acting at the crossroads of fundamental signalling cascades.

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Figure 1: miR-15 and miR-16 control Nodal/activin responsiveness by acting as inhibitors of Acvr2a expression.
Figure 2: miR-15 antagonizes Spemann’s organizer development.
Figure 3: miR-15 and miR-16 are required to set the size of the organizer by limiting Nodal responsiveness.
Figure 4: miR-15 and miR-16 and Acvr2a show complementary domains of expression.
Figure 5: miR-15 and miR-16 are negatively regulated by Wnt/β-catenin signalling.

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Acknowledgements

We thank G. Bressan and D. Volpin for discussion. This work is supported by grants from AIRC, TELETHON-Italy, MIUR (CoFin, FIRB), ASI, the ISS-Stem cells program and Swissbridge to S.P. A.M. is a recipient of an EU-Marie Curie RTN fellowship (epiplast carcinoma). We are grateful to J. Moulton for help in the design of miRNA morpholinos; C. Niehrs, N. Ueno, J. Green, W. Knochel and M. Asashima for gifts of plasmids; and W. Vale for the anti-Acvr2a antibody and F. Fagotto for protocols. L.Z. is a recipient of a post-doctoral contract from the University of Padua and M.I. is a recipient of a TOYOBO Biotechnology Foundation (Japan) grant.

Author Contributions G.M. identified Acvr2a as a target of miR-15 and miR-16. G.M., L.Z. and M.I. performed the Xenopus assays. M.C. and G.M. carried out experiments in human cells. U.T. and L.Z. performed the immunohistochemistry analysis. S.P. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Stefano Piccolo.

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Martello, G., Zacchigna, L., Inui, M. et al. MicroRNA control of Nodal signalling. Nature 449, 183–188 (2007). https://doi.org/10.1038/nature06100

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