Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration

Nature Genetics volume 43, pages 204–211 (2011)Cite this article

Subjects

Abstract

microRNAs (miRNAs) function as genetic rheostats to control gene output. Based on their role as modulators, it has been postulated that miRNAs canalize development and provide genetic robustness. Here, we uncover a previously unidentified regulatory layer of chemokine signaling by miRNAs that confers genetic robustness on primordial germ cell (PGC) migration. In zebrafish, PGCs are guided to the gonad by the ligand Sdf1a, which is regulated by the sequestration receptor Cxcr7b. We find that miR-430 regulates sdf1a and cxcr7 mRNAs. Using target protectors, we demonstrate that miR-430–mediated regulation of endogenous sdf1a (also known as cxcl12a) and cxcr7b (i) facilitates dynamic expression of sdf1a by clearing its mRNA from previous expression domains, (ii) modulates the levels of the decoy receptor Cxcr7b to avoid excessive depletion of Sdf1a and (iii) buffers against variation in gene dosage of chemokine signaling components to ensure accurate PGC migration. Our results indicate that losing miRNA-mediated regulation can expose otherwise buffered genetic lesions leading to developmental defects.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: miR-430 target validation of chemokine signaling genes.
Figure 2: Target protectors prevent miRNA-mediated repression of target GFP reporters.
Figure 3: Blocking miR-430–mediated repression of sdf1a and cxcr7b causes PGC mislocalization and expanded sdf1a expression.
Figure 4: miR-430 and Cxcr7b act in a functionally redundant manner to refine Sdf1a expression.
Figure 5: miR-430 buffers against overexpression of the chemokine signaling components.
Figure 6: Regulation by miR-430 guards against variation in gene dosage.
Figure 7: Model of miR-430–mediated repression of chemokine signaling.

Similar content being viewed by others

References

  1. Kitano, H. Biological robustness. Nat. Rev. Genet. 5, 826–837 (2004).

    Article  CAS  Google Scholar 

  2. Maheshri, N. & O'Shea, E.K. Living with noisy genes: how cells function reliably with inherent variability in gene expression. Annu. Rev. Biophys. Biomol. Struct. 36, 413–434 (2007).

    Article  CAS  Google Scholar 

  3. Hornstein, E. & Shomron, N. Canalization of development by microRNAs. Nat. Genet. 38 Suppl, S20–S24 (2006).

    Article  CAS  Google Scholar 

  4. Raser, J.M. & O'Shea, E.K. Noise in gene expression: origins, consequences, and control. Science 309, 2010–2013 (2005).

    Article  CAS  Google Scholar 

  5. Raj, A. & van Oudenaarden, A. Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135, 216–226 (2008).

    Article  CAS  Google Scholar 

  6. Herranz, H. & Cohen, S.M. MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. Genes Dev. 24, 1339–1344 (2010).

    Article  CAS  Google Scholar 

  7. Sangster, T.A. et al. HSP90 affects the expression of genetic variation and developmental stability in quantitative traits. Proc. Natl. Acad. Sci. USA 105, 2963–2968 (2008).

    Article  CAS  Google Scholar 

  8. Rutherford, S.L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998).

    Article  CAS  Google Scholar 

  9. Bartel, D.P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233 (2009).

    Article  CAS  Google Scholar 

  10. Stark, A., Brennecke, J., Bushati, N., Russell, R.B. & Cohen, S.M. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3′UTR evolution. Cell 123, 1133–1146 (2005).

    Article  CAS  Google Scholar 

  11. Bartel, D.P. & Chen, C.Z. Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat. Rev. Genet. 5, 396–400 (2004).

    Article  CAS  Google Scholar 

  12. Wu, C.I., Shen, Y. & Tang, T. Evolution under canalization and the dual roles of microRNAs: a hypothesis. Genome Res. 19, 734–743 (2009).

    Article  CAS  Google Scholar 

  13. Li, X., Cassidy, J.J., Reinke, C.A., Fischboeck, S. & Carthew, R.W. A microRNA imparts robustness against environmental fluctuation during development. Cell 137, 273–282 (2009).

    Article  CAS  Google Scholar 

  14. Raz, E. Primordial germ-cell development: the zebrafish perspective. Nat. Rev. Genet. 4, 690–700 (2003).

    Article  CAS  Google Scholar 

  15. Raz, E. & Mahabaleshwar, H. Chemokine signaling in embryonic cell migration: a fisheye view. Development 136, 1223–1229 (2009).

    Article  CAS  Google Scholar 

  16. Naumann, U. et al. CXCR7 functions as a scavenger for CXCL12 and CXCL11. PLoS ONE 5, e9175 (2010).

    Article  Google Scholar 

  17. Boldajipour, B. et al. Control of chemokine-guided cell migration by ligand sequestration. Cell 132, 463–473 (2008).

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Giraldez, A.J. et al. Zebrafish MiR-430 promotes deadenylation and clearance of maternal mRNAs. Science 312, 75–79 (2006).

    Article  CAS  Google Scholar 

  20. Nakahara, K. et al. Targets of microRNA regulation in the Drosophila oocyte proteome. Proc. Natl. Acad. Sci. USA 102, 12023–12028 (2005).

    Article  CAS  Google Scholar 

  21. Choi, W.Y., Giraldez, A.J. & Schier, A.F. Target protectors reveal dampening and balancing of nodal agonist and antagonist by miR-430. Science 318, 271–274 (2007).

    Article  CAS  Google Scholar 

  22. Doitsidou, M. et al. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111, 647–659 (2002).

    Article  CAS  Google Scholar 

  23. Weidinger, G. et al. Regulation of zebrafish primordial germ cell migration by attraction towards an intermediate target. Development 129, 25–36 (2002).

    CAS  PubMed  Google Scholar 

  24. Busch-Nentwich, E. et al. Sanger Institute Zebrafish Mutation Resource targeted knock-out mutants phenotype and image data submission. ZFIN Direct Data Submission (2010).

  25. Knaut, H., Werz, C., Geisler, R. & Nusslein-Volhard, C. A zebrafish homologue of the chemokine receptor Cxcr4 is a germ-cell guidance receptor. Nature 421, 279–282 (2003).

    Article  CAS  Google Scholar 

  26. Mangan, S. & Alon, U. Structure and function of the feed-forward loop network motif. Proc. Natl. Acad. Sci. USA 100, 11980–11985 (2003).

    Article  CAS  Google Scholar 

  27. Wall, M.E., Dunlop, M.J. & Hlavacek, W.S. Multiple functions of a feed-forward-loop gene circuit. J. Mol. Biol. 349, 501–514 (2005).

    Article  CAS  Google Scholar 

  28. Alon, U. Network motifs: theory and experimental approaches. Nat. Rev. Genet. 8, 450–461 (2007).

    Article  CAS  Google Scholar 

  29. Knaut, H., Blader, P., Strähle, U. & Schier, A.F. Assembly of trigeminal sensory ganglia by chemokine signaling. Neuron 47, 653–666 (2005).

    Article  CAS  Google Scholar 

  30. David, N.B. et al. Molecular basis of cell migration in the fish lateral line: role of the chemokine receptor CXCR4 and of its ligand, SDF1. Proc. Natl. Acad. Sci. USA 99, 16297–16302 (2002).

    Article  CAS  Google Scholar 

  31. Siekmann, A.F., Standley, C., Fogarty, K.E., Wolfe, S.A. & Lawson, N.D. Chemokine signaling guides regional patterning of the first embryonic artery. Genes Dev. 23, 2272–2277 (2009).

    Article  CAS  Google Scholar 

  32. Nair, S. & Schilling, T.F. Chemokine signaling controls endodermal migration during zebrafish gastrulation. Science 322, 89–92 (2008).

    Article  CAS  Google Scholar 

  33. Mizoguchi, T., Verkade, H., Heath, J.K., Kuroiwa, A. & Kikuchi, Y. Sdf1/Cxcr4 signaling controls the dorsal migration of endodermal cells during zebrafish gastrulation. Development 135, 2521–2529 (2008).

    Article  CAS  Google Scholar 

  34. Luster, A.D. Chemokines–chemotactic cytokines that mediate inflammation. N. Engl. J. Med. 338, 436–445 (1998).

    Article  CAS  Google Scholar 

  35. Petit, I., Jin, D. & Rafii, S. The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis. Trends Immunol. 28, 299–307 (2007).

    Article  CAS  Google Scholar 

  36. Broxmeyer, H.E. et al. Transgenic expression of stromal cell-derived factor-1/CXC chemokine ligand 12 enhances myeloid progenitor cell survival/antiapoptosis in vitro in response to growth factor withdrawal and enhances myelopoiesis in vivo. J. Immunol. 170, 421–429 (2003).

    Article  CAS  Google Scholar 

  37. Aiuti, A., Webb, I.J., Bleul, C., Springer, T. & Gutierrez-Ramos, J.C. The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J. Exp. Med. 185, 111–120 (1997).

    Article  CAS  Google Scholar 

  38. Vandercappellen, J., Van Damme, J. & Struyf, S. The role of CXC chemokines and their receptors in cancer. Cancer Lett. 267, 226–244 (2008).

    Article  CAS  Google Scholar 

  39. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  Google Scholar 

  40. Svoboda, P. & Flemr, M. The role of miRNAs and endogenous siRNAs in maternal-to-zygotic reprogramming and the establishment of pluripotency. EMBO Rep. 11, 590–597 (2010).

    Article  CAS  Google Scholar 

  41. Rosa, A., Spagnoli, F.M. & Brivanlou, A.H. The miR-430/427/302 family controls mesendodermal fate specification via species-specific target selection. Dev. Cell 16, 517–527 (2009).

    Article  CAS  Google Scholar 

  42. Varghese, J. & Cohen, S.M. microRNA miR-14 acts to modulate a positive autoregulatory loop controlling steroid hormone signaling in Drosophila. Genes Dev. 21, 2277–2282 (2007).

    Article  CAS  Google Scholar 

  43. Li, Y., Wang, F., Lee, J.A. & Gao, F.B. microRNA-9a ensures the precise specification of sensory organ precursors in Drosophila. Genes Dev. 20, 2793–2805 (2006).

    Article  CAS  Google Scholar 

  44. Hilgers, V., Bushati, N. & Cohen, S.M. Drosophila microRNAs 263a/b confer robustness during development by protecting nascent sense organs from apoptosis. PLoS Biol. 8, e1000396 (2010).

    Article  Google Scholar 

  45. Zhang, F., Gu, W., Hurles, M.E. & Lupski, J.R. Copy number variation in human health, disease, and evolution. Annu. Rev. Genomics Hum. Genet. 10, 451–481 (2009).

    Article  CAS  Google Scholar 

  46. Friedman, R.C., Farh, K.K., Burge, C.B. & Bartel, D.P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009).

    Article  CAS  Google Scholar 

  47. Wienholds, E., Koudijs, M.J., van Eeden, F.J., Cuppen, E. & Plasterk, R.H. The microRNA-producing enzyme Dicer1 is essential for zebrafish development. Nat. Genet. 35, 217–218 (2003).

    Article  CAS  Google Scholar 

  48. Boldajipour, B., Mahabaleshwar, H. & Kardash, E. Control of chemokine-guided cell migration by ligand sequestration. Cell 132, 463–473 (2008).

    Article  CAS  Google Scholar 

  49. Mishima, Y. et al. Zebrafish miR-1 and miR-133 shape muscle gene expression and regulate sarcomeric actin organization. Genes Dev. 23, 619–632 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Patnode for fish husbandry, C. Takacs and C. Stahlhut for discussion and critical reading of the manuscript, H. Xue for analysis of the Sdf1a 3′ UTR and D. Stemple for cxcr7b mutant zebrafish. This work was supported by the National Research Service Award US National Institutes of Health (NIH)/National Institute of General Medicine Sciences T32 GM007223 Training Grant (A.A.S.), NIH grants R01GM081602-03/03S1, the Yale Scholar program, the Pew Scholars Program in Biomedical Sciences (A.J.G.) and a Whitehead Fellowship Award (H.K.).

Author information

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA

    Alison A Staton & Antonio J Giraldez

  2. Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA

    Holger Knaut

  3. Yale Stem Cell Center, Yale University School of Medicine, New Haven, Connecticut, USA

    Antonio J Giraldez

Authors
  1. Alison A Staton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Holger Knaut
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio J Giraldez
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.A.S. and A.J.G. designed the experiments and interpreted the results. A.A.S. performed all experiments except the genetic interactions in the cxcr7b and cxcr4b mutant backgrounds, which were performed by H.K. A.A.S. wrote the manuscript with input from H.K. and A.J.G.

Corresponding author

Correspondence to Antonio J Giraldez.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, Supplementary Table 1 and Supplementary Note (PDF 1932 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Staton, A., Knaut, H. & Giraldez, A. miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration. Nat Genet 43, 204–211 (2011). https://doi.org/10.1038/ng.758

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.758

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing