The pathogenesis of nephrogenic rests and wilms tomour: Role of WT1 in arrested development
Bibliographic record
Abstract
The mammalian kidney is derived from progenitor cells in intermediate mesoderm.During embryogenesis, progenitor cells expressing the Wilms tumour suppressor gene, WT1, are induced to differentiate in response to WNT signals from the ureteric bud.Hereditary forms of Wilms tumour arise from WT1-negative developmentally arrested renal progenitor cells called nephrogenic rests, which precludes the beta-catenin pathway response.Recently, a subset of Wilms tumours has been associated with bi-allelic mutations in DICER1 or DROSHA, crucial to microRNA biogenesis.In this thesis, we show that WT1 primes nephron progenitor cells for differentiation by transcriptionally suppressing Enhancer of Zeste homolog 2 (EZH2), the key component in the Polycomb repressor complex 2 (PRC2) responsible for epigenetic silencing through.The repression of EZH2 leads to the reduction of the histone H3 lysine 27 trimethylation mark (H3K27me3) that silences beta-catenin expression (CTNNB1).As a result, amMSC acquire responsiveness to WNT9b and increase expression of genes that mark the onset of nephron differentiation.Furthermore, we show that WT1 also regulates EZH2 posttranscriptionally in concert with miRNAs.We observed a change in miRNA expression in the presence of WT1.miRNAs targeting the 3'UTR of EZH2 and other Polycomb associated transcripts were up-regulated in the cell lines expressing WT1.The +KTS isoform of WT1 binds the 5'UTR of EZH2 and interacts directly with the miRNA-containing RNA-induced silencing complex (miRISC) to enhance post-transcriptional inhibition.These observations suggest that bi-allelic loss of WT1 sustains the inhibitory histone methylation state that characterizes Wilms tumours.Moreover, they suggest an novel alternative mechanism of action through which WT1 can regulate the transition from resting to activated nephron progenitor cell during nephrogenesis.Finally, our findings also present a plausible
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.000 |
| 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".