PreprintCited by 920Glioma Diagnosis and TreatmentCancer-related Molecular PathwaysDevelopmental Biology and Gene Regulation

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

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Marino, Silvia, Vooijs, Marc, van der Gulden, Hanneke, Jonkers, Jos, Berns, Anton·2000·Genes & Development

Abstract

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.

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Crossref · 10.1101/gad.14.8.994

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  • Microglia start to proliferate and colonize the CNS parenchyma before the blood-brain barrier is formed.

    “and they start to proliferate and colonize the CNS parenchyma before the blood-brain barrier is formed10.”

    From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [10]

    The Abstract and Discussion discuss astrocytes, neural precursors, and cerebellar development, not microglial colonization. Searches for microglial proliferation, CNS colonization, and blood-brain barrier formation found no passage addressing their timing. Page numbers are not available in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • Microglia develop from myeloid progenitors in the yolk sac at embryonic day E8.5.

    “Microglia develop from their myeloid progenitors in the yolk sac at embryonic day (E)8.5”

    From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [10]

    The Discussion and the section on EGL precursor cells describe neural and cerebellar precursors, not the origin of microglia. Searches for microglia, yolk-sac myeloid progenitors, and E8.5 found no passage addressing the claim. (LLM, conf=0.78)

    Experimental — accuracy not yet measured
  • Combined loss of Trp53 and Rb produces more tumours in mutant mice.

    “When loss of Trp53 and Rb are combined, more tumours develop in mutant mice24,147–149 but it becomes difficult to dissect the respective roles of these two potent tumour suppressors.”

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Authors
Marino, S., Vooijs, M., van der Gulden, H., Jonkers, J., & Berns, A.
Affiliations
The Netherlands Cancer Institute (NL)
Venue
Genes & Development
Published
2000-04-15
Volume
14
Issue
8
Pages
994-1004
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2151199834
Cited by
920
References
63
Citations by year
2026: 36 · 2025: 56 · 2024: 54 · 2023: 37 · 2022: 87 · 2021: 57 · 2020: 31 · 2019: 40 · 2018: 29 · 2017: 33 · 2016: 33 · 2015: 28 · 2014: 33 · 2013: 27 · 2012: 27
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
medulloblastoma, p53, retinoblastoma protein, Rb inactivation, external granular layer, cerebellum, tumor suppressor, mouse tumor model, Cre-loxP system, GFAP-Cre, embryonal tumors, cerebellar development, pediatric brain tumors
MeSH terms
Animals, Astrocytes, beta-Galactosidase, Cerebellar Neoplasms, Cerebellum, Glial Fibrillary Acidic Protein, Medulloblastoma, Mice, Mutant Strains, Mutation, Plasmids, Promoter Regions, Genetic, Tissue Distribution, Transcription, Genetic, Viral Proteins, Genes, p53, Genes, Retinoblastoma, In Situ Hybridization, Transgenes, Integrases, Mice

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