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| 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
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| 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.
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| 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.
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| 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 |
| E-mail(s) |
u.schueller@uke.de
|
| 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 |
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| Platforms (1) |
| GPL30650 |
Infinium Mouse Methylation BeadChip |
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| Samples (6)
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| GSM7706474 |
Control Cerebellum E16.5_205659810062_R03C01 |
| GSM7706475 |
Control Cerebellum E16.5_205659810062_R05C01 |
| GSM7706476 |
Control Cerebellum E16.5_205659810062_R01C01 |
| GSM7706477 |
Mutant Cerebellum E16.5_205659810062_R02C01 |
| GSM7706478 |
Mutant Cerebellum E16.5_205659810062_R06C01 |
| GSM7706479 |
Mutant Cerebellum E16.5_205659810062_R01C02 |
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| Relations |
| BioProject |
PRJNA1004337 |
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