Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells.
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.
Yang
Zeng-Jie
ZJ
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Ellis
Tammy
T
Markant
Shirley L
SL
Read
Tracy-Ann
TA
Kessler
Jessica D
JD
Bourboulas
Melissa
M
Schüller
Ulrich
U
Machold
Robert
R
Fishell
Gord
G
Rowitch
David H
DH
Wainwright
Brandon J
BJ
Wechsler-Reya
Robert J
RJ
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*
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