Discovery of thyrocyte heterogeneity reveals an essential role of Notch signaling in thyroid function and mammalian homeostasis
Bibliographic record
Abstract
SUMMARY The thyroid functions at the apex of a web of endocrine organs that control cell growth, differentiation and metabolic homeostasis. Thyroid dysregulation significantly impacts human health in myriad ways with thyroid diseases standing as the most common endocrine disorder. Despite the essential role of the thyroid in human health, a high-resolution view of the cellular composition as well as molecular mechanisms that govern function of this crucial organ have been lacking. Employing the first single-cell analyses of adult mouse thyroid, we here report the discovery of unexpected thyrocyte heterogeneity, specifically three distinct thyrocyte subtypes marked by different metabolic and Notch signaling patterns. Using a battery of pharmacologic and genetic methods, we find that selective inhibition of Notch ligands and receptors disrupts thyrocyte mitochondrial activity and ROS production, thus decreasing levels of circulating thyroid hormones, inducing hypothyroidism and disrupting whole-body thermoregulation. We find an enriched frequency of hypothyroidism in children with Alagille Syndrome, a genetic disorder marked by Notch loss-of-function mutations, suggesting that our Notch-thyroid mechanisms are relevant in humans and directly account for Alagille hypothyroidism. Overall, our work reveals that Notch, although classically described as a developmental pathway that determines cell fate, controls homeostasis and thermoregulation in the adult through a mitochondria-based mechanism in a subset of thyrocytes. Our fine-grained picture of the thyroid unveils a novel understanding of this key metabolic organ and provides clinically impactful insights into its pathological dysfunctions.
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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 | 0.001 |
| 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".