| First Author | Tsiami F | Year | 2025 |
| Journal | Sci Rep | Volume | 15 |
| Issue | 1 | Pages | 26091 |
| PubMed ID | 40681754 | Mgi Jnum | J:370168 |
| Mgi Id | MGI:8225455 | Doi | 10.1038/s41598-025-11857-3 |
| Citation | Tsiami F, et al. (2025) SMARCA5 is required for the development of granule cell neuron precursors and Sonic Hedgehog Medulloblastoma growth. Sci Rep 15(1):26091 |
| abstractText | 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. |
