title: Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells.
abstract: Medulloblastoma is the most common malignant brain tumor in children, but the cells from which it arises remain unclear. Here we examine the origin of medulloblastoma resulting from mutations in the Sonic hedgehog (Shh) pathway. We show that activation of Shh signaling in neuronal progenitors causes medulloblastoma by 3 months of age. Shh pathway activation in stem cells promotes stem cell proliferation but only causes tumors after commitment to-and expansion of-the neuronal lineage. Notably, tumors initiated in stem cells develop more rapidly than those initiated in progenitors, with all animals succumbing by 3-4 weeks. These studies suggest that medulloblastoma can be initiated in progenitors or stem cells but that Shh-induced tumorigenesis is associated with neuronal lineage commitment.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zeng-Jie
authors.initials: ZJ
authors.lastname: Yang
authors.forename: Tammy
authors.initials: T
authors.lastname: Ellis
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Markant
authors.forename: Tracy-Ann
authors.initials: TA
authors.lastname: Read
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Kessler
authors.forename: Melissa
authors.initials: M
authors.lastname: Bourboulas
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.forename: Robert
authors.initials: R
authors.lastname: Machold
authors.forename: Gord
authors.initials: G
authors.lastname: Fishell
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Wainwright
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D017353:Gene Deletion; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D019426:Integrases / Q000378:metabolism; D008527:Medulloblastoma / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology; D000072079:Patched Receptors; D010641:Phenotype; D011230:Precancerous Conditions / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000235:genetics*; D013234:Stem Cells / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D019426:Integrases; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C500943:Atoh1 protein, mouse; C045073:Cre recombinase