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 t hey are associated with substantial mortality and morbidity. The molecular pathogenesis as well as the ontogeny of these neoplasms is still poorly und erstood. We have generated a mouse model for medulloblastoma by Cre-LoxP-me diated inactivation of Rb and p53 tumor suppressor genes in the cerebellar external granular layer (EGL) cells. GFAP-Cre-mediated recombination was fo und both in astrocytes and in immature precursor cells of the EGL in the de veloping cerebellum. GFAP-Cre;Rb-LoxP/LoxP;p53(-/-) (or LoxP/LoxP) mice dev eloped highly aggressive embryonal tumors of the cerebellum with typical fe atures of medulloblastoma. These tumors were identified as early as 7 weeks of age on the outer surface of the molecular layer, corresponding to the l ocation of the EGL cells during development. Our results demonstrate that l oss of function of RE is essential for medulloblastoma development in the m ouse and strongly support the hypothesis that medulloblastomas arise from m ultipotent precursor cells located in the EGL.