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Dual and opposing roles of primary cilia in medulloblastoma development


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.

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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.


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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 We thank S. Wong, J. Reiter, D. Cano and S. Cervantes-Roldan for sharing unpublished data.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.

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Authors and Affiliations



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.

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Correspondence to Arturo Alvarez-Buylla.

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Han, YG., Kim, H., Dlugosz, A. et al. Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15, 1062–1065 (2009).

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