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.

  • Letter
  • Published:

Dual and opposing roles of primary cilia in medulloblastoma development

Abstract

Recent work has shown that primary cilia are essential for Hedgehog (Hh) signaling during mammalian development1,2,3,4,5,6,7,8,9. It is also known that aberrant Hh signaling can lead to cancer10, but the role of primary cilia in oncogenesis is not known. Cerebellar granule neuron precursors (GNPs) can give rise to medulloblastomas, the most common malignant brain tumor in children11,12. The primary cilium and Hh signaling are required for GNP proliferation8,12,13,14,15. We asked whether primary cilia in GNPs have a role in medulloblastoma growth in mice. Genetic ablation of primary cilia blocked medulloblastoma formation when this tumor was driven by a constitutively active Smoothened protein (Smo), an upstream activator of Hh signaling. In contrast, removal of cilia was required for medulloblastoma growth by a constitutively active glioma-associated oncogene family zinc finger-2 (GLI2), a downstream transcription factor. Thus, primary cilia are either required for or inhibit medulloblastoma formation, depending on the initiating oncogenic event. Remarkably, the presence or absence of cilia was associated with specific variants of human medulloblastomas; primary cilia were found in medulloblastomas with activation in HH or WNT signaling but not in most medulloblastomas in other distinct molecular subgroups. Primary cilia could serve as a diagnostic tool and provide new insights into the mechanism of tumorigenesis.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Kif3a is required for SmoM2-driven medulloblastoma formation.
Figure 2: Kif3a suppresses GLI2ΔN-driven medulloblastoma formation.
Figure 3: Primary cilia are present in a subset of human medulloblastomas.

Similar content being viewed by others

References

  1. Corbit, K.C. et al. Vertebrate Smoothened functions at the primary cilium. Nature 437, 1018–1021 (2005).

    Article  CAS  Google Scholar 

  2. Haycraft, C.J. et al. Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet. 1, e53 (2005).

    Article  Google Scholar 

  3. Rohatgi, R., Milenkovic, L. & Scott, M.P. Patched1 regulates hedgehog signaling at the primary cilium. Science 317, 372–376 (2007).

    Article  CAS  Google Scholar 

  4. Han, Y.G. et al. Hedgehog signaling and primary cilia are required for the formation of adult neural stem cells. Nat. Neurosci. 11, 277–284 (2008).

    Article  CAS  Google Scholar 

  5. Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).

    Article  CAS  Google Scholar 

  6. Liu, A., Wang, B. & Niswander, L.A. Mouse intraflagellar transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132, 3103–3111 (2005).

    Article  CAS  Google Scholar 

  7. May, S.R. et al. Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev. Biol. 287, 378–389 (2005).

    Article  CAS  Google Scholar 

  8. Spassky, N. et al. Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool. Dev. Biol. 317, 246–259 (2008).

    Article  CAS  Google Scholar 

  9. Huangfu, D. & Anderson, K.V. Cilia and Hedgehog responsiveness in the mouse. Proc. Natl. Acad. Sci. USA 102, 11325–11330 (2005).

    Article  CAS  Google Scholar 

  10. Varjosalo, M. & Taipale, J. Hedgehog: functions and mechanisms. Genes Dev. 22, 2454–2472 (2008).

    Article  CAS  Google Scholar 

  11. Gilbertson, R.J. & Ellison, D.W. The origins of medulloblastoma subtypes. Annu. Rev. Pathol. 3, 341–365 (2008).

    Article  CAS  Google Scholar 

  12. Chizhikov, V.V. et al. Cilia proteins control cerebellar morphogenesis by promoting expansion of the granule progenitor pool. J. Neurosci. 27, 9780–9789 (2007).

    Article  CAS  Google Scholar 

  13. Dahmane, N. & Ruiz i Altaba, A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 126, 3089–3100 (1999).

    PubMed  Google Scholar 

  14. Wallace, V.A. Purkinje-cell–derived Sonic hedgehog regulates granule neuron precursor cell proliferation in the developing mouse cerebellum. Curr. Biol. 9, 445–448 (1999).

    Article  CAS  Google Scholar 

  15. Wechsler-Reya, R.J. & Scott, M.P. Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999).

    Article  CAS  Google Scholar 

  16. Goodrich, L.V., Milenkovic, L., Higgins, K.M. & Scott, M.P. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277, 1109–1113 (1997).

    Article  CAS  Google Scholar 

  17. Hallahan, A.R. et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. 64, 7794–7800 (2004).

    Article  CAS  Google Scholar 

  18. Mao, J. et al. A novel somatic mouse model to survey tumorigenic potential applied to the Hedgehog pathway. Cancer Res. 66, 10171–10178 (2006).

    Article  CAS  Google Scholar 

  19. Oliver, T.G. et al. Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132, 2425–2439 (2005).

    Article  CAS  Google Scholar 

  20. Schüller, U. et al. Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma. Cancer Cell 14, 123–134 (2008).

    Article  Google Scholar 

  21. Yang, Z.J. et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell 14, 135–145 (2008).

    Article  CAS  Google Scholar 

  22. Rosenbaum, J.L. & Witman, G.B. Intraflagellar transport. Nat. Rev. Mol. Cell Biol. 3, 813–825 (2002).

    Article  CAS  Google Scholar 

  23. Marszalek, J.R. et al. Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175–187 (2000).

    Article  CAS  Google Scholar 

  24. Marszalek, J.R., Ruiz-Lozano, P., Roberts, E., Chien, K.R. & Goldstein, L.S. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc. Natl. Acad. Sci. USA 96, 5043–5048 (1999).

    Article  CAS  Google Scholar 

  25. Haycraft, C.J. et al. Intraflagellar transport is essential for endochondral bone formation. Development 134, 307–316 (2007).

    Article  CAS  Google Scholar 

  26. Murcia, N.S. et al. The Oak Ridge polycystic kidney (orpk) disease gene is required for left-right axis determination. Development 127, 2347–2355 (2000).

    CAS  Google Scholar 

  27. Huangfu, D. & Anderson, K.V. Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133, 3–14 (2006).

    Article  CAS  Google Scholar 

  28. Pasca di Magliano, M. et al. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 20, 3161–3173 (2006).

    Article  CAS  Google Scholar 

  29. Roessler, E. et al. A previously unidentified amino-terminal domain regulates transcriptional activity of wild-type and disease-associated human GLI2. Hum. Mol. Genet. 14, 2181–2188 (2005).

    Article  CAS  Google Scholar 

  30. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    Article  CAS  Google Scholar 

  31. Lam, C.W. et al. A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18, 833–836 (1999).

    Article  CAS  Google Scholar 

  32. Thompson, M.C. et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J. Clin. Oncol. 24, 1924–1931 (2006).

    Article  CAS  Google Scholar 

  33. Northcott, P.A. et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat. Genet. 41, 465–472 (2009).

    Article  CAS  Google Scholar 

  34. Corbit, K.C. et al. Kif3a constrains β-catenin–dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10, 70–76 (2008).

    Article  CAS  Google Scholar 

  35. Gerdes, J.M. et al. Disruption of the basal body compromises proteasomal function and perturbs intracellular Wnt response. Nat. Genet. 39, 1350–1360 (2007).

    Article  CAS  Google Scholar 

  36. Simons, M. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat. Genet. 37, 537–543 (2005).

    Article  CAS  Google Scholar 

  37. Wong, S.Y. et al. Nat. Med. advance online publication, doi:10.1038/nm.2011 (23 August 2009).

  38. Martinelli, D.C. & Fan, C.M. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev. 21, 1231–1243 (2007).

    Article  CAS  Google Scholar 

  39. Zhuo, L. et al. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis 31, 85–94 (2001).

    Article  CAS  Google Scholar 

  40. Pfaffl, M.W., Horgan, G.W. & Dempfle, L. Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acid Res. 30, e36 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

We thank L.S. Goldstein at the University of California–San Diego for providing us with Kif3afl/fl mice; D. Rowitch at UCSF for SmoM2fl/+ mice; B. Yoder at the University of Alabama–Birmingham for Ift88fl/fl mice; C. Cowdrey and the Neurological Surgery Tissue Bank at UCSF for human medulloblastoma samples; R. Segal and C. Stiles at Harvard University for Zic–specific and Olig2–specific antibodies; and A. Ruiz i Altaba at University of Geneva Medical School for Gli1 cDNA. We thank S. Wong, J. Reiter, D. Cano and S. Cervantes-Roldan for sharing unpublished data. We thank S. Vandenberg for helping with assessing the tumor types; J. Morris, K. Blaschke and M. Sachs for helping with quantitative RT-PCR; R. Romero for technical assistance; and D. Rowitch, J. Reiter, S Wong, R. Ihrie, S. Nader and T. Nguyen for comments on the manuscript. Y.-G.H. was, in part, supported by Mark Linder/American Brain Tumor Association Fellowship. The work was supported by grants from the US National Institutes of Health (NS28478 and HD32116), John G Bowes Research Fund and a grant from the Goldhirsh Foundation to A. A.-B. Confocal microscopy at Diabetes & Endocrinology Research Center. Microscopy and Imaging Core was supported by an US National Institutes of Health grant P30 DK063720.

Author information

Authors and Affiliations

Authors

Contributions

Y.-G.H. designed and performed most experiments. H.J.K. performed western blot analysis. A.A.D. provided CLEG2 mice. D.W.E. and R.J.G. provided human medulloblastoma tissue microarrays that were analyzed previously for gene expression profiling. A.A.-B. supervised the project. Y.-G.H. and A.A.-B. wrote the manuscript. All authors commented on the manscript.

Corresponding author

Correspondence to Arturo Alvarez-Buylla.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–6 and Supplementary Table 1 (PDF 890 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, YG., Kim, H., Dlugosz, A. et al. Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15, 1062–1065 (2009). https://doi.org/10.1038/nm.2020

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2020

This article is cited by

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