Embryonic Stem Cell-Derived Cardiomyogenesis: A Novel Role for Calreticulin as a Regulator
Bibliographic record
Abstract
A role for calreticulin, an endoplasmic reticulum (ER)-resident, Ca(2+)-binding chaperone, has recently emerged in the context of cardiomyogenesis. We previously proposed calreticulin to be a novel cardiac fetal gene, because calreticulin knockout causes embryonic lethality in mice as a result of cardiac defects, it is transiently activated during heart development, and heart-targeted overexpression of constitutively active calcineurin in calreticulin-null mice rescues the lethal phenotype. Calreticulin affects Ca(2+) homeostasis and expression of adhesion-related genes. Using cardiomyocytes derived from both calreticulin-null and wild-type embryonic stem (ES) cells, we show here that cardiomyogenesis from calreticulin-null ES cells is accelerated but deregulated, such that the myofibrils of calreticulin-null cardiomyocytes become disorganized and disintegrate with time in culture. We have previously shown that the disorganization of the actin cytoskeleton in calreticulin-null cells may be explained, at least in part, by the downregulation of adhesion proteins, implying that calreticulin ablation causes adhesion-related defects. Here, upon examination of adhesion proteins, we found that vinculin is downregulated in calreticulin-null cardiomyocytes. We also found c-Src activity to be higher in calreticulin-null cardiomyocytes than in wild-type cardiomyocytes, and c-Src activity is affected by both calreticulin and [Ca(2+)]. Finally, we show that calreticulin and calsequestrin, the major Ca(2+) storage proteins of the ER and sarcoplasmic reticulum, respectively, exhibit alternate distributions. This suggests that calreticulin may have a housekeeping role to play in mature cardiomyocytes as well as during cardiomyogenesis. We propose here that calreticulin, an ER Ca(2+) storage protein, is a crucial regulator of cardiomyogenesis whose presence is required for controlled cardiomyocyte development from ES cells.
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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".