SMARCA5 is required for the development of granule cell neuron precursors and Sonic Hedgehog Medulloblastoma growth
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".