title: 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 development. It is also known that aberrant Hh signaling can lead to cancer, 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 children. The primary cilium and Hh signaling are required for GNP proliferation. 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.
authors.affiliation: Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research University of California-San Francisco (UCSF), California, USA.
authors.forename: Young-Goo
authors.initials: YG
authors.lastname: Han
authors.forename: Hong Joo
authors.initials: HJ
authors.lastname: Kim
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez-Buylla
mesh_terms: D000818:Animals; D002528:Cerebellar Neoplasms / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D002923:Cilia / Q000473:pathology / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins / Q000502:physiology; D006801:Humans; D016547:Kinesins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D008527:Medulloblastoma / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction; D000072086:Smoothened Receptor; D051153:Wnt Proteins / Q000502:physiology; D000075746:Zinc Finger Protein Gli2
chemical_list: C082593:GLI2 protein, human; C000618551:Gli2 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D051153:Wnt Proteins; D000075746:Zinc Finger Protein Gli2; C528900:glial fibrillary astrocytic protein, mouse; D016547:Kinesins
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