Acquisition of granule neuron precursor identity is a critical determinant of progenitor cell competence to form Shh-induced medulloblastoma.
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.
Schüller
Ulrich
U
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Heine
Vivi M
VM
Mao
Junhao
J
Kho
Alvin T
AT
Dillon
Allison K
AK
Han
Young-Goo
YG
Huillard
Emmanuelle
E
Sun
Tao
T
Ligon
Azra H
AH
Qian
Ying
Y
Ma
Qiufu
Q
Alvarez-Buylla
Arturo
A
McMahon
Andrew P
AP
Rowitch
David H
DH
Ligon
Keith L
KL
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*
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