Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum.
Medulloblastomas are among the most common malignancies in childhood, and they are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly understood. We have generated a mouse model for medulloblastoma by Cre-LoxP-mediated inactivation of Rb and p53 tumor suppressor genes in the cerebellar external granular layer (EGL) cells. GFAP-Cre-mediated recombination was found both in astrocytes and in immature precursor cells of the EGL in the developing cerebellum. GFAP-Cre;Rb(LoxP/LoxP);p53(-/- or LoxP/LoxP) mice developed highly aggressive embryonal tumors of the cerebellum with typical features of medulloblastoma. These tumors were identified as early as 7 weeks of age on the outer surface of the molecular layer, corresponding to the location of the EGL cells during development. Our results demonstrate that loss of function of RB is essential for medulloblastoma development in the mouse and strongly support the hypothesis that medulloblastomas arise from multipotent precursor cells located in the EGL.
Marino
S
S
Division of Molecular Genetics and Centre of Biomedical Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
Vooijs
M
M
van Der Gulden
H
H
Jonkers
J
J
Berns
A
A
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D016161:Genes, Retinoblastoma / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D017403:In Situ Hybridization; D019426:Integrases / Q000378:metabolism; D008527:Medulloblastoma / Q000139:chemically induced*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010957:Plasmids; D011401:Promoter Regions, Genetic; D014018:Tissue Distribution; D014158:Transcription, Genetic; D019076:Transgenes; D014764:Viral Proteins; D001616:beta-Galactosidase / Q000378:metabolism
D005904:Glial Fibrillary Acidic Protein; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D001616:beta-Galactosidase