Pax3 target gene recognition occurs through distinct modes that are differentially affected by disease‐associated mutations
Bibliographic record
Abstract
The paired box protein Pax3 is an essential regulator of muscle and neural crest-derived cell types, including melanocytes. Within this lineage, Pax3 has been shown to regulate the genes encoding microphthalmia-associated transcription factor (Mitf) and tyrosinase-related protein-1 (Trp-1), despite each having dissimilar Pax3 recognition sequences. We have, therefore, examined the structural requirements for Pax3 binding to the MITF and TRP-1 promoter elements, focusing on the contribution of the paired domain and homeodomain to Pax3 target site recognition. Unexpectedly, although the MITF element is characterized by suboptimal recognition motifs for the paired domain and homeodomain, it sustains a higher level of Pax3 binding than TRP-1, which contains a canonical paired domain site. The basis for this difference involves a context-dependent cooperative binding event requiring both the paired domain and homeodomain, while the paired domain alone is sufficient for TRP-1 recognition. Significantly, the analysis of Waardenburg syndrome mutations reveals marked disparity in their effects on MITF and TRP-1 binding that further underscores mechanistic differences in their interaction with Pax3. Importantly, these mutations also exert distinct effects on the ability of Pax3 to regulate reporter genes fused to either the MITF or TRP-1 promoters. Our results, therefore, establish that Pax3 can regulate target genes through alternate modes of DNA recognition that are differentially impacted by disease-causing mutations, which together have important implications for understanding Pax3-regulated gene networks.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".