Canonical Notch signaling is not required for the growth of Hedgehog pathway-induced medulloblastoma.
Current treatment for medulloblastoma is successful in more than half of all cases but results in substantial disability in survivors. Accordingly, there is considerable interest in drugs that may target specific signaling pathways activated in the tumors, with inhibitors of both the Hedgehog and Notch pathways currently proposed as possible therapeutics. Here, we tested the hypothesis that Notch pathway inhibition in vivo may block the formation of Hedgehog-dependent medulloblastoma. We took the general approach of using a cre recombinase under the control of the GFAP promoter to generate medulloblastoma in mice carrying a conditional Ptc1 allele and introduced a conditional RBP-J allele to ablate canonical Notch signaling. Loss of RBP-J from the developing cerebellum led to a modest loss of stem cells and an overall developmental delay. These phenotypes could be partially compensated by activation of the Hedgehog pathway. Hedgehog-dependent medulloblastoma were not blocked by loss of RBP-J, indicating that canonical Notch signaling is not required for tumor initiation and growth in this model.
Julian
E
E
Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.
Dave
R K
RK
Robson
J P
JP
Hallahan
A R
AR
Wainwright
B J
BJ
D000483:Alleles; D000818:Animals; D002455:Cell Division; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology*; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins / Q000378:metabolism*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology
D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009419:Nerve Tissue Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C497571:Rbpj protein, mouse; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; C528900:glial fibrillary astrocytic protein, mouse