SMARCA5 is required for the development of granule cell neuron precursors and Sonic Hedgehog Medulloblastoma growth

TL;DR

This study shows that the SMARCA5 gene is essential for the development of certain brain cells and for the growth of a specific type of brain tumor called Sonic Hedgehog Medulloblastoma.

Contribution

The study identifies SMARCA5 as a novel genetic dependency in Sonic Hedgehog Medulloblastoma using CRISPR-Cas9 screening and mouse models.

Findings

SMARCA5 knockout inhibits SHH pathway activation and tumor cell proliferation in SHH-MB.

Conditional deletion of SMARCA5 in granule cell neuron precursors reduces their proliferative capacity and causes cerebellar hypoplasia.

Loss of SMARCA5 in a mouse model of SHH-MB leads to prolonged survival of tumor-bearing mice.

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.

The online version contains supplementary material available at 10.1038/s41598-025-11857-3.

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