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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References
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004)
Ambros, V. The functions of animal microRNAs. Nature 431, 350–355 (2004)
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)
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)
Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000)
Niehrs, C. Regionally specific induction by the Spemann-Mangold organizer. Nature Rev. Genet. 5, 425–434 (2004)
Schohl, A. & Fagotto, F. β-catenin, MAPK and Smad signaling during early Xenopus development. Development 129, 37–52 (2002)
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)
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)
Tao, Q. et al. Maternal wnt11 activates the canonical wnt signaling pathway required for axis formation in Xenopus embryos. Cell 120, 857–871 (2005)
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)
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)
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)
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)
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)
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)
Vize, P. D. DNA sequences mediating the transcriptional response of the Mix.2 homeobox gene to mesoderm induction. Dev. Biol. 177, 226–231 (1996)
Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85–89 (1997)
Krek, A. et al. Combinatorial microRNA target predictions. Nature Genet. 37, 495–500 (2005)
John, B. et al. Human MicroRNA targets. PLoS Biol. 2, e363 (2004)
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)
Watanabe, T. et al. Stage-specific expression of microRNAs during Xenopus development. FEBS Lett. 579, 318–324 (2005)
Krutzfeldt, J., Poy, M. N. & Stoffel, M. Strategies to determine the biological function of microRNAs. Nature Genet. 38 (Suppl). S14–S19 (2006)
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)
Piccolo, S. et al. The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals. Nature 397, 707–710 (1999)
Shi, R. & Chiang, V. L. Facile means for quantifying microRNA expression by real-time PCR. Biotechniques 39, 519–525 (2005)
Feldman, B. et al. Lefty antagonism of Squint is essential for normal gastrulation. Curr. Biol. 12, 2129–2135 (2002)
Meno, C. et al. Mouse Lefty2 and zebrafish antivin are feedback inhibitors of nodal signaling during vertebrate gastrulation. Mol. Cell 4, 287–298 (1999)
Zhang, L. et al. Zebrafish Dpr2 inhibits mesoderm induction by promoting degradation of nodal receptors. Science 306, 114–117 (2004)
Giraldez, A. J. et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833–838 (2005)
Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003)
Tang, F. et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev. 21, 644–648 (2007)
Cordenonsi, M. et al. Integration of TGF-β and Ras/MAPK signaling through p53 phosphorylation. Science 315, 840–843 (2007)
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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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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DOI: https://doi.org/10.1038/nature06100
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