CS-08 * SONIC HEDGEHOG SIGNALING PROTECTS ATOH1 FROM DEGRADATION MEDIATED BY THE HECT DOMAIN E3 UBIQUITIN LIGASE HUWE1 IN CEREBELLAR GRANULE NEURON PROGENITORS
Bibliographic record
Abstract
Cerebellar development requires a balance between several biological processes including proliferation, differentiation and migration. The pro-neural basic helix-loop-helix transcription factor Atoh1 was shown to be a key player controlling the formation of granule neuron progenitors (GNPs). Its uncontrolled levels in collaboration with Sonic Hedgehog (SHH) activation are critical for medulloblastoma (MB) formation, a devastating pediatric tumor that originates from the cerebellum. Because Atoh1 acts as a lineage dependency transcription factor in MB, mechanisms controlling Atoh1 expression are keen interest in the field. However, how this master transcription factor is regulated has remained poorly understood. In our study, we dissected the machinery that regulates Atoh1 in GNPs and in MB. We first identified two phosphorylation sites that regulate Atoh1 stability and function in GNPs. Second, combining tandem affinity purification with an Atoh1 phospho-deficient mutant and multidimensional protein identification technology analysis, we identified the E3 ubiquitin ligase Huwe1 as Atoh1 binding partner. We showed that Atoh1 physically interacted with Huwe1 in a phospho-dependent manner in GNPs, mediating its ubiquitylation whereas Cre-mediated deletion of Huwe1 from postnatal GNPs increased Atoh1 protein levels. Next, we uncovered that SHH regulates Atoh1 stability by preventing its phospho-dependent degradation by Huwe1. In the tumoral context, consistent with Atoh1 upregulation in MBs driven by SHH activation, Huwe1 was found downregulated in primary mouse tumors. In human SHH MB, low HUWE1 expression was found specifically associated with poor prognosis. Overall, our results reveal that SHH and Atoh1 contribute to a positive autoregulatory loop promoting neuronal precursor expansion. Consequently, Huwe1 alterations in SHH MB illustrate the disruption of this developmental mechanism in cancer. This crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a new collaborative network that could be further targeted in 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 | 0.001 |
| 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".