Dystroglycan function in development and neuromuscular disease : a study by gene targeting
Bibliographic record
Abstract
The dystrophin associated protein (DAP) complex has been implicated in such basic physiological processes as the maintenance of cellular homeostasis, the assembly of basement membranes (BM), and synaptogenesis. The dystroglycans, alpha and beta, constitute the functional core of the DAP complex since they establish the transmembrane link between dystrophin, whose mutations lead to Duchenne (DMD) or Becker (BMD) muscular dystrophy, and the extracellular matrix (ECM). The alpha and beta subunits of dystroglycan result from posttranslational processing of a single propeptide encoded by DAG1. No clinical cases or animal models have been identified with spontaneous mutations in that gene. Therefore, to gain insight to the function of dystroglycans I have used gene targeting to disrupt the coding sequence of Dag1 in murine embryonic stem (ES) cells. We find that dystroglycans are critical in the early stages of development and that a null mutation in Dag1 results in embryonic lethality at embryonic day (E) 6.5 because of a disruption in Reichert's BM. In culture however, the absence of dystroglycan in ES cells targeted for both Dag1 alleles does not obviously hinder their developmental potential. Consequently, I reasoned that it might be possible to circumvent the early lethality observed in 'classical' knockout mice, by injecting Dag1-null ES cells into wild-type blastocysts to generate chimeric mice only partially devoid of dystroglycan. Several chimeric mice developed to maturity and Dag1 -null ES cells were found to contribute extensively to the hindlimb musculature thus allowing the analysis of dystroglycan depleted muscles. These muscles are severely dystrophic, have low levels of dystrophin and a disrupted residual DAP complex, but have apparently normal BMs. Chimeric muscles also have disrupted neuromuscular junctions. In culture, myotubes derived from Dag1-null ES cells form clusters of acetylcholine receptors (AChRs) but these occupy a surface area three time
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".