Early life starvation and Hedgehog-related signaling activate innate immunity downstream of daf-18/PTEN and lin-35/Rb causing developmental pathology in adult C. elegans
Bibliographic record
Abstract
Early life experiences such as malnutrition can affect development and adult disease risk, but the molecular basis of such protracted effects is poorly understood. In the nematode C. elegans, extended starvation during the first larval stage causes the development of germline tumors and other abnormalities in the adult gonad, limiting reproductive success. Insulin/IGF signaling (IIS) acts through WNT signaling and lipid metabolism to promote starvation-induced gonad abnormalities, but IIS-independent modifiers have not been identified. The tumor suppressor daf-18/PTEN inhibits IIS to suppress starvation-induced abnormalities, but we show that it also acts independently of IIS via lin-35/Rb, another tumor suppressor, to suppress such abnormalities. We found that lin-35/Rb and the rest of the DREAM complex repress transcription of the Hedgehog (Hh) signaling homologs ptr-23/PTCH-related, wrt-1/Hh-like, and wrt-10/Hh-like, which promote starvation-induced abnormalities. These Hh-related genes transcriptionally activate several genes associated with innate immunity in adults, which also promote starvation-induced gonad abnormalities. Surprisingly, we found that in addition to causing developmental abnormalities, early-life starvation induces an innate immune response later in life, leading to increased resistance to bacterial and intracellular pathogens. This work identifies a critical tumor-suppressor function of daf-18/PTEN independent of IIS, and it defines a regulatory network, including lin-35/Rb and DREAM, Hh-related signaling, and innate immunity pathways, that affects development of tumors and other developmental abnormalities resulting from early life starvation. By revealing that early-life starvation increases immunity later in life, this work suggests a fitness tradeoff between pathogen resistance and developmental robustness.
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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".