title: Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.
abstract: Whether the brain tumor medulloblastoma originates from stem cells or restricted progenitor cells is unclear. To investigate this, we activated oncogenic Hedgehog (Hh) signaling in multipotent and lineage-restricted central nervous system (CNS) progenitors. We observed that normal unipotent cerebellar granule neuron precursors (CGNPs) derive from hGFAP(+) and Olig2(+) rhombic lip progenitors. Hh activation in a spectrum of early- and late-stage CNS progenitors generated similar medulloblastomas, but not other brain cancers, indicating that acquisition of CGNP identity is essential for tumorigenesis. We show in human and mouse medulloblastoma that cells expressing the glia-associated markers Gfap and Olig2 are neoplastic and retain features of embryonic-type granule lineage progenitors. Thus, oncogenic Hh signaling promotes medulloblastoma from lineage-restricted granule cell progenitors.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Vivi M
authors.initials: VM
authors.lastname: Heine
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.forename: Alvin T
authors.initials: AT
authors.lastname: Kho
authors.forename: Allison K
authors.initials: AK
authors.lastname: Dillon
authors.forename: Young-Goo
authors.initials: YG
authors.lastname: Han
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Huillard
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Ying
authors.initials: Y
authors.lastname: Qian
authors.forename: Qiufu
authors.initials: Q
authors.lastname: Ma
authors.forename: Arturo
authors.initials: A
authors.lastname: Alvarez-Buylla
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Keith L
authors.initials: KL
authors.lastname: Ligon
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019070:Cell Lineage; D054022:Cerebrum / Q000473:pathology; D003433:Crosses, Genetic; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D000076104:Oligodendrocyte Transcription Factor 2; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D013234:Stem Cells / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C405708:OLIG2 protein, human; C509239:SHH protein, human; C465570:Shh protein, mouse; C491022:Smo protein, mouse