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MicroRNA control of Nodal signalling


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.


  1. Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)

    CAS  Article  Google Scholar 

  2. Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004)

    ADS  CAS  Article  Google Scholar 

  3. Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005)

    CAS  Article  Google Scholar 

  4. Xie, X. et al. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434, 338–345 (2005)

    ADS  CAS  Article  Google Scholar 

  5. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000)

    CAS  Article  Google Scholar 

  6. Niehrs, C. Regionally specific induction by the Spemann-Mangold organizer. Nature Rev. Genet. 5, 425–434 (2004)

    CAS  Article  Google Scholar 

  7. Schohl, A. & Fagotto, F. β-catenin, MAPK and Smad signaling during early Xenopus development. Development 129, 37–52 (2002)

    CAS  Article  Google Scholar 

  8. Faure, S., Lee, M. A., Keller, T., ten Dijke, P. & Whitman, M. Endogenous patterns of TGFβ superfamily signaling during early Xenopus development. Development 127, 2917–2931 (2000)

    CAS  Article  Google Scholar 

  9. De Robertis, E. M., Larrain, J., Oelgeschlager, M. & Wessely, O. The establishment of Spemann’s organizer and patterning of the vertebrate embryo. Nature Rev. Genet. 1, 171–181 (2000)

    CAS  Article  Google Scholar 

  10. Tao, Q. et al. Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell 120, 857–871 (2005)

    CAS  Article  Google Scholar 

  11. Heasman, J., Kofron, M. & Wylie, C. β-catenin signaling activity dissected in the early Xenopus embryo: a novel antisense approach. Dev. Biol. 222, 124–134 (2000)

    CAS  Article  Google Scholar 

  12. Heasman, J. et al. Overexpression of cadherins and underexpression of β-catenin inhibit dorsal mesoderm induction in early Xenopus embryos. Cell 79, 791–803 (1994)

    CAS  Article  Google Scholar 

  13. Agius, E., Oelgeschlager, M., Wessely, O., Kemp, C. & De Robertis, E. M. Endodermal Nodal-related signals and mesoderm induction in Xenopus. Development 127, 1173–1183 (2000)

    CAS  Article  Google Scholar 

  14. Pogoda, H. M., Solnica-Krezel, L., Driever, W. & Meyer, D. The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr. Biol. 10, 1041–1049 (2000)

    CAS  Article  Google Scholar 

  15. Cha, Y. R., Takahashi, S. & Wright, C. V. Cooperative non-cell and cell autonomous regulation of Nodal gene expression and signaling by Lefty/Antivin and Brachyury in Xenopus. Dev. Biol. 290, 246–264 (2006)

    CAS  Article  Google Scholar 

  16. Norris, D. P. & Robertson, E. J. Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements. Genes Dev. 13, 1575–1588 (1999)

    CAS  Article  Google Scholar 

  17. Vize, P. D. DNA sequences mediating the transcriptional response of the Mix.2 homeobox gene to mesoderm induction. Dev. Biol. 177, 226–231 (1996)

    CAS  Article  Google Scholar 

  18. Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85–89 (1997)

    ADS  CAS  Article  Google Scholar 

  19. Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005)

    CAS  Article  Google Scholar 

  20. John, B. et al. Human MicroRNA targets. PLoS Biol. 2, e363 (2004)

    Article  Google Scholar 

  21. Song, J. et al. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev. Biol. 213, 157–169 (1999)

    CAS  Article  Google Scholar 

  22. Watanabe, T. et al. Stage-specific expression of microRNAs during Xenopus development. FEBS Lett. 579, 318–324 (2005)

    CAS  Article  Google Scholar 

  23. Krutzfeldt, J., Poy, M. N. & Stoffel, M. Strategies to determine the biological function of microRNAs. Nature Genet. 38 (Suppl). S14–S19 (2006)

    Article  Google Scholar 

  24. Flynt, A. S., Li, N., Thatcher, E. J., Solnica-Krezel, L. & Patton, J. G. Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate. Nature Genet. 39, 259–263 (2007)

    CAS  Article  Google Scholar 

  25. Piccolo, S. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397, 707–710 (1999)

    ADS  CAS  Article  Google Scholar 

  26. Shi, R. & Chiang, V. L. Facile means for quantifying microRNA expression by real-time PCR. Biotechniques 39, 519–525 (2005)

    CAS  Article  Google Scholar 

  27. Feldman, B. et al. Lefty antagonism of Squint is essential for normal gastrulation. Curr. Biol. 12, 2129–2135 (2002)

    CAS  Article  Google Scholar 

  28. Meno, C. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4, 287–298 (1999)

    CAS  Article  Google Scholar 

  29. Zhang, L. et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science 306, 114–117 (2004)

    ADS  CAS  Article  Google Scholar 

  30. Giraldez, A. J. et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833–838 (2005)

    ADS  CAS  Article  Google Scholar 

  31. Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003)

    CAS  Article  Google Scholar 

  32. Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007)

    CAS  Article  Google Scholar 

  33. Cordenonsi, M. et al. Integration of TGF-β and Ras/MAPK signaling through p53 phosphorylation. Science 315, 840–843 (2007)

    ADS  CAS  Article  Google Scholar 

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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).

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