title: The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation.
abstract: Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors.
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: Hai-Kun
authors.initials: HK
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Thorsten
authors.initials: T
authors.lastname: Belz
authors.forename: Dagmar
authors.initials: D
authors.lastname: Bock
authors.forename: Andrea
authors.initials: A
authors.lastname: Takacs
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Barbus
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015870:Gene Expression; D016158:Genes, p53 / Q000235:genetics; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000473:pathology
chemical_list: C490258:Nr2e1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear