title: The nuclear receptor TLX is required for gliomagenesis within the adult neurogenic niche.
abstract: Neural stem cells (NSCs) continually generate functional neurons in the adult brain. Due to their ability to proliferate, deregulated NSCs or their progenitors have been proposed as the cells of origin for a number of primary central nervous system neoplasms, including infiltrating gliomas. The orphan nuclear receptor TLX is required for proliferation of adult NSCs, and its upregulation promotes brain tumor formation. However, it is unknown whether TLX is required for gliomagenesis. We examined the genetic interactions between TLX and several tumor suppressors, as well as the role of TLX-dependent NSCs during gliomagenesis, using mouse models. Here, we show that TLX is essential for the proliferation of adult NSCs with a single deletion of p21, p53, or Pten or combined deletion of Pten and p53. While brain tumors still form in Tlx mutant mice, these tumors are less infiltrative and rarely associate with the adult neurogenic niches, suggesting a non-stem-cell origin. Taken together, these results indicate a critical role for TLX in NSC-dependent gliomagenesis and implicate TLX as a therapeutic target to inhibit the development of NSC-derived brain tumors.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zou
authors.forename: Wenze
authors.initials: W
authors.lastname: Niu
authors.forename: Song
authors.initials: S
authors.lastname: Qin
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Burns
authors.forename: Chun-Li
authors.initials: CL
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D009367:Neoplasm Staging; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D057093:Orphan Nuclear Receptors; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C088601:NR2E1 protein, human; C490258:Nr2e1 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D016159:Tumor Suppressor Protein p53; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse