Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum.

By Silvia Marino, M. Vooijs, H. Gulden, J. Jonkers, A. Berns. Genes & Development, 2000

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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.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/2d552b2bbf0dd4bab3dad74cfb5e3c2a1b4806c5

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Citations in the corpus

hGFAP‐cre transgenic mice for manipulation of glial and neuronal function in vivo (2001, background): “Strikingly similar results were reported by Marino et al. (2000) in their study of Rb/p53 mutations and cerebellar medulloblastoma, using a transgene that consisted of Cre under the control of regulatory elements from the mouse GFAP gene and tested with the same lacZ reporter lines as those used…”
The WHO Classification of Tumors of the Nervous System (2002, background): “Strongly suggestive is the development of medulloblastomas on the cerebellar surface of p53-null mutant (knockout) mice with somatic inactivation of the retinoblastoma gene (Rb) in the external granular layer (47).”
Non-cell-autonomous tumor suppression by p53 (2013, background): “Although the GFAP promoter is primarily expressed in the adult astroglia, GFAP-Cre; p53 conditional knockout mice show no increased evidence of brain tumors or any other disease (Marino et al., 2000), thus allowing us dissect the role of p53 in HSCs without other confounding phenotypes.”
Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features (2008, background): “Although RB1 mutations have never been detected in other medulloblastomas [64], some experimental tumor models suggest a role for the RB pathway in this tumor.”
Electroporation and RNA interference in the rodent retina in vivo and in vitro (2003, background): “Using Cre-expressing retroviruses and a retinal progenitor-specific Cre transgenic mouse line (Chx10-Cre) mated to RbLox mice [8], we previously showed that the retinal defects first identified by Maandag and colleagues reflect a cell-autonomous requirement for Rb at specific developmental stages in”