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Simultaneous Brg1 Knockout and MYCN Overexpression in Cerebellar Granule Neuron Precursors Is Insufficient to Drive Tumor Formation but Temporarily Enhances their Proliferation and Delays their Migration

Authors
  • Holdhof, Dörthe1, 2
  • On, Ji Hoon2
  • Schoof, Melanie1, 2
  • Göbel, Carolin1, 2
  • Schüller, Ulrich1, 2, 1
  • 1 University Medical Center Hamburg-Eppendorf,
  • 2 Research Institute Children’s Cancer Center Hamburg,
Type
Published Article
Journal
Cerebellum (London, England)
Publisher
Springer US
Publication Date
Jan 02, 2021
Volume
20
Issue
3
Pages
410–419
Identifiers
DOI: 10.1007/s12311-020-01219-2
PMID: 33387268
PMCID: PMC8213679
Source
PubMed Central
Keywords
Disciplines
  • Original Article
License
Unknown

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. According to the World Health Organization (WHO) classification of central nervous system (CNS) tumors, this embryonal tumor is divided into a wingless (WNT)-activated, Sonic hedgehog (SHH)-activated, and non-WNT/non-SHH entity. The latter is poorly defined but frequently carries mutations in Brahma-related gene 1 ( BRG1 ) or amplifications of MYCN . Here, we investigated whether a combination of a Brg1 knockout and an overexpression of MYCN in cerebellar granule neuron precursors or multipotent neural stem cells is sufficient to drive brain tumor formation in mice. To this end, we generated Math1-creER T2 ::Brg1 fl/fl ::lslMYCN and hGFAP-cre::Brg1 fl/fl ::lslMYCN mice, respectively. We did not observe brain tumor formation in any of these models. hGFAP-cre::Brg1 fl/fl ::lslMYCN mice revealed severe CNS abnormalities with short survival, similar to the situation with a sole loss of Brg1 , as we previously described. Investigation of Math1-creER T2 ::Brg1 fl/fl ::lslMYCN mice with a tamoxifen induction at postnatal day 3 revealed a regular survival but significant increase in cerebellar granule neuron precursor proliferation, followed by a delayed inward migration of these cells. This is in stark contrast to the hypoplastic cerebellum that we previously observed after embryonic deletion of Brg1 in Math1 positive cerebellar granule neurons. Our results indicate a time-specific function of Brg1 in cerebellar granule neuron precursors. Yet, the exact temporal and spatial origin of non-WNT/non-SHH MB remains unclear. Supplementary Information The online version contains supplementary material available at 10.1007/s12311-020-01219-2.

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