Olig2-regulated lineage-restricted pathway controls replication competence in neural stem cells and malignant glioma.
Recent studies have identified stem cells in brain cancer. However, their relationship to normal CNS progenitors, including dependence on common lineage-restricted pathways, is unclear. We observe expression of the CNS-restricted transcription factor, OLIG2, in human glioma stem and progenitor cells reminiscent of type C transit-amplifying cells in germinal zones of the adult brain. Olig2 function is required for proliferation of neural progenitors and for glioma formation in a genetically relevant murine model. Moreover, we show p21(WAF1/CIP1), a tumor suppressor and inhibitor of stem cell proliferation, is directly repressed by OLIG2 in neural progenitors and gliomas. Our findings identify an Olig2-regulated lineage-restricted pathway critical for proliferation of normal and tumorigenic CNS stem cells.
Ligon
Keith L
KL
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Huillard
Emmanuelle
E
Mehta
Shwetal
S
Kesari
Santosh
S
Liu
Hongye
H
Alberta
John A
JA
Bachoo
Robert M
RM
Kane
Michael
M
Louis
David N
DN
Depinho
Ronald A
RA
Anderson
David J
DJ
Stiles
Charles D
CD
Rowitch
David H
DH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000378:metabolism*; D001932:Brain Neoplasms / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005434:Flow Cytometry; D005910:Glioma / Q000473:pathology*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D000076104:Oligodendrocyte Transcription Factor 2; D013234:Stem Cells / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D049452:Green Fluorescent Proteins; D008156:Luciferases; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C493956:CDKN1A protein, human; C512773:Olig2 protein, mouse