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Series GSE240627 Query DataSets for GSE240627
Status Public on Apr 17, 2024
Title SMARCA4 loss and mutated β-catenin induce proliferative lesions in the murine embryonic cerebellum
Organism Mus musculus
Experiment type Methylation profiling by array
Summary Almost all medulloblastomas (MB) of the Wingless/Int-1 (WNT) subgroup are characterized by hotspot mutations in CTNNB1, and mouse models have convincingly demonstrated the tumor-initiating role of these mutations. Additional alterations in SMARCA4 are detected in around 20 % of WNT MB but their functional role is mostly unknown. We therefore amended previously described Blbp-cre::Ctnnb1(ex3)fl/wt mice by the introduction of a floxed Smarca4 allele. In contrast to existing literature, even mutated β-catenin on its own in our Blbp-cre::Ctnnb1(ex3)fl/wt mice induced severe developmental phenotypes including a thinned cerebral cortex, hydrocephalus, missing cerebellar layering, and non-proliferative cell accumulations in brain stem and cerebellum. An additional homozygous loss of SMARCA4 even resulted in prenatal death for most mice. Interestingly, Blbp-cre::Ctnnb1(ex3)fl/wt::Smarca4fl/fl mutants developed big proliferative lesions in the cerebellum that evolved from E13.5 to E16.5. Histological and molecular analysis of these lesions by DNA methylation analysis and single-cell RNA sequencing suggest an origin in early undifferentiated SOX2-positive cerebellar progenitors. Furthermore, upregulation of WNT signaling and altered actin/cytoskeleton organization and neuronal differentiation were evident in mutant cells. In vitro, cells harboring alterations in both Ctnnb1 and Smarca4 were negatively selected and did not show tumorigenic potential after transplantation in adult recipient mice. However, mutant cells displayed increased proliferation compared to controls in cerebellar explant culture, indicating an important role of the embryonic microenvironment in the development of lesions. Altogether, these results represent an important first step in unravelling tumorigenic mechanisms induced by aberrant WNT signaling and a SMARCA4 deficiency.
Overall design We performed global DNA methylation analysis of E16.5 embryos (Blbp-cre::Ctnnb1(ex3)fl/wt::Smarca4fl/fl mutants and cre-negative controls) to unravel epigenetically deregulated pathways in the histologically evident cerebellar lesions of mutants.
Contributor(s) Göbel C, Schoof M, Holdhof D, Spohn M, Schüller U
Citation(s) 38383496
Submission date Aug 10, 2023
Last update date Apr 18, 2024
Contact name Ulrich Schüller
Organization name University Medical Center Hamburg-Eppendorf
Lab Research Institute Children's Cancer Center
Street address Martinistraße 52
City Hamburg
ZIP/Postal code 20251
Country Germany
Platforms (1)
GPL30650 Infinium Mouse Methylation BeadChip
Samples (6)
GSM7706474 Control Cerebellum E16.5_205659810062_R03C01
GSM7706475 Control Cerebellum E16.5_205659810062_R05C01
GSM7706476 Control Cerebellum E16.5_205659810062_R01C01
BioProject PRJNA1004337

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Supplementary file Size Download File type/resource
GSE240627_RAW.tar 45.7 Mb (http)(custom) TAR (of IDAT)
GSE240627_processed_data.txt.gz 9.4 Mb (ftp)(http) TXT
Processed data included within Sample table

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