SMARCA5 is required for the development of granule cell neuron precursors and Sonic Hedgehog Medulloblastoma growth
Abstract Medulloblastoma constitutes a molecularly diverse group of malignant embryonal brain tumors. Sonic hedgehog molecular group of medulloblastoma (SHH-MB) is a highly heterogeneous tumor entity, characterized by constitutive activation of the SHH signaling pathway. Due to lack of suitable cell...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-11857-3 |
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| Summary: | Abstract Medulloblastoma constitutes a molecularly diverse group of malignant embryonal brain tumors. Sonic hedgehog molecular group of medulloblastoma (SHH-MB) is a highly heterogeneous tumor entity, characterized by constitutive activation of the SHH signaling pathway. Due to lack of suitable cell line models, little is known about genetic dependencies in SHH-MB outside of the SHH pathway. By performing a CRISPR-Cas9 dropout screen in SMB21 cells derived from SHH-MB in Ptch +/− mice, we aimed to identify genetic vulnerabilities in SHH-MB. Among the top scored gene hits, members of the SNF2-family of ATP-dependent chromatin remodelers including Smarca5 emerged as genetic dependencies in SHH-MB, and we validate that Smarca5 knockout inhibits SHH pathway activation and SHH-MB cell proliferation. Additional genetic ablation experiments in vivo revealed that conditional deletion of Smarca5 in cerebellar granule cell neuron precursors (GCNPs), the cell origin of SHH-MB, significantly reduces the proliferative capacity of GCNPs and leads to cerebellar hypoplasia in mice. Furthermore, loss of Smarca5 in GCNPs in an established mouse model of SHH-MB results in prolonged survival of tumor bearing mice. Our data underline the critical role of SMARCA5 during the development of the cerebellum and the pathogenesis of SHH-MB. |
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| ISSN: | 2045-2322 |