Cytokine control of systemic hypoxia tolerance in <i>Drosophila</i>
Bibliographic record
Abstract
Summary Systemic hypoxia—reduction in oxygen supply to all tissues and organs—occurs in both physiological and pathological conditions in animals. Under these conditions, organisms must adapt their physiology to ensure proper functioning and survival. While extensive research has characterized how individual cells sense and adapt to low oxygen conditions, the mechanisms that coordinate whole-body responses to systemic hypoxia remain poorly understood. In this study, we uncover an interorgan signaling response mediated by the cytokine Unpaired-3 (upd3) that is important for systemic hypoxia tolerance in Drosophila . We demonstrate that hypoxia rapidly induces upd3 expression and activates JAK/STAT signaling in both larvae and adults. Interestingly, we discovered a sex-specific requirement for this pathway, with females requiring upd3 for hypoxia survival while males do not. We also identify the intestine as a critical source of hypoxia-induced upd3 and show that gut-derived upd3 signals to the fat body and oenocytes to mediate hypoxia tolerance by promoting nitric oxide synthase expression. Furthermore, we reveal an unexpected role for the canonical hypoxia response transcription factor HIF-1α/sima as a molecular brake, preventing lethal upd3 overproduction, revealing that hypoxia survival requires precise cytokine dosage control. Our findings define a gut-to-fat/oenocyte signaling axis that coordinates systemic hypoxia adaptation, highlighting the complex interplay between classic hypoxia response pathways and cytokine signaling in maintaining organismal homeostasis during oxygen limitation. This work provides important insights into how organisms adapt to systemic hypoxia, with potential implications for understanding systemic hypoxia-related human pathologies such as respiratory disorders and sleep apnea.
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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) | 0.001 | 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".