The extracellular matrix protein agrin is essential for epicardial epithelial-to-mesenchymal transition during heart development
Bibliographic record
Abstract
Abstract During embryonic heart development, epicardial cells residing within the outer layer of the heart undergo epithelial-mesenchymal transition (EMT) and migrate into the myocardium to support and stimulate organ growth and morphogenesis. Disruption of epicardial EMT results in aberrant heart formation and embryonic lethality. Despite being an essential process during development, the regulation of epicardial EMT is poorly understood. Here we report EMT on the epicardial surface of the embryonic heart at subcellular resolution using scanning electron microscopy (SEM). We identified high- and low-EMT regions within the mesothelial layer of the epicardium and an association with key components of the extracellular matrix (ECM). The ECM basement membrane-associated proteoglycan agrin was found to localize in the epicardium in regions actively undergoing EMT. Deletion of agrin resulted in impaired EMT and compromised development of the epicardium, accompanied by down-regulation of the epicardial EMT regulator WT1. Agrin enhanced EMT in human embryonic stem cell-derived epicardial-like cells by decreasing β-catenin and promoting pFAK localization at focal adhesions. In addition, agrin promoted the aggregation of its receptor dystroglycan to the Golgi apparatus in murine epicardial cells and loss of agrin resulted in dispersal of dystroglycan throughout the epicardial cells in embryos, disrupting basement membrane integrity and impairing EMT. Our results provide new insights into the role of the ECM in heart development, and implicate agrin as a critical regulator of EMT, functioning to ensure dystroglycan connects signals between the ECM and activated epicardial cells. Summary statement The basement membrane-associated proteoglycan agrin regulates epicardial epithelia-to-mesenchyme transition (EMT) through dystroglycan localizing on the Golgi apparatus. This ensures ECM and cytoskeletal connectivity and mechanical integrity of the transitioning epicardium and has important implications for the role of the extracellular matrix (ECM) in heart development.
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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".