Notch Signaling Is Required for Mast Cell Development in the Zebrafish.
Bibliographic record
Abstract
Abstract Abstract 3588 Poster Board III-525 The molecular pathways regulating mast cell (MC) development in vertebrates remain to be elucidated. The Notch signaling pathway is highly conserved in all metazoans and has been implicated in regulating hematopoietic stem cell induction and lineage cell fate decisions. Notch receptors and their ligands are expressed in a number of hematopoietic cells, including MCs. We were the first to identify zebrafish MC equivalents (Dobson et al., Blood 2008) and examine vertebrate MC transcriptional regulation in vivo. These studies demonstrated the significance of carboxypeptidase A 5 (cpa5) as a zebrafish MC-specific marker. Co-localization studies reveal zebrafish notch3 (a homologue of human NOTCH3) is expressed in a proportion of cpa5 positive cells in 7 day old embryos. Moreover, the zebrafish Notch signaling mutant, mind bomb, displays profound loss of cpa-5 expression, as do wild type zebrafish embryos treated with Compound E (Cpd E), a gamma-secretase inhibitor that blocks Notch signaling. We previously identified pu.1 and gata2 as essential transcription factors for early MC development. Interestingly, we observed a dose-dependent response, with reduced cpa5 and gata2 but preserved pu.1 expression at 50 μM Cpd E, compared with profound decreased expression of all these factors, as well as gata1 and mpo at 75 μM Cpd E. These data suggest a particular role for Notch signaling in regulating MC development, as well as a potentially broader role in regulating the myeloid and erythroid lineages. These studies are currently being validated through reciprocal experiments overexpressing notch mRNA in wild type embryos and rescue experiments overexpressing the notch intracellular domain and the above-mentioned transcription factors in Notch deficient embryos (mind bomb and Cpd E treated). We have also developed a transgenic zebrafish line expressing the human c-KIT D816V mutation found in systemic mastocytosis, which exhibits increased mast cells at the expense of erythroid cells, features in keeping with the human condition. These transgenic fish provide an opportunity to examine if Notch pathway inhibition alone, or in combination with other therapies, such as those targeting the c-KIT kinase, have a therapeutic impact in this condition. Parallel approaches in a human mastocytosis cell line are also being undertaken. These studies promise key insight into the role of Notch signaling in MC development and the opportunity to use the zebrafish as an in vivo model for identifying novel therapeutic strategies in MC diseases. Disclosures: Ferrando: Merck, Pfizer: Research Funding.
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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 | 0.000 | 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) | 0.000 | 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".