<i>Fgf8</i> dosage and tissue interactions contribute to jaw asymmetry in disease
Bibliographic record
Abstract
Asymmetry in presence or severity of jaw defects is commonly observed in craniofacial congenital disorders, such as cleft palate. Fgf8 is a secreted signaling factor that contributes to the growth and development of many tissues, including the limbs and jaw. Using an allelic series of Fgf8 mutant mice to generate embryos with 5 distinct genotypes and Fgf8 dosages, we investigated the effects of reductions in Fgf8 dosage on size and symmetry of the jaw and limbs. Bone length was measured and compared left versus right in limbs and isolated dentaries of WT, heterozygous, and mutant neonatal skeletons. Mutant mandibles are smaller and much more variable in size than WT or heterozygote mandibles and exhibit directional asymmetry, with the left side more severely affected. In contrast, no apparent asymmetry was observed in the limbs, however, mutant limbs are smaller than in the other genotypes. These data suggest jaw development is more susceptible to reduction in Fgf8 dosage than is limb development. To investigate mechanisms underlying differential susceptibility to Fgf8 reduction, we compared Fgf expression in mandibles and limbs. To investigate mechanisms underlying directional asymmetry in the jaw related to Fgf8 reduction, we evaluated cell death and jaw patterning. Fgf8 mutants exhibit increased cell death in neural crest progenitors at E9.5 relative to WT, however, there is no difference in L‐R asymmetry between mutants and WT individuals. We do, however, observe asymmetry in jaw patterning (e.g, Dlx5 expression) in mutant embryos at E10.5. We also find asymmetry in first pharyngeal pouch (PP1) morphology. We hypothesize that early developmental interactions between the heart field (which is known to asymmetrically express Fgf8 ) and prospective pharyngeal endoderm fields contribute to asymmetry in PP1 development, which ultimately lead to asymmetry in jaw patterning and morphogenesis. Our data suggest that asymmetry in craniofacial defects may result from early asymmetries in gene expression coupled with developmental tissue interactions. Support or Funding Information R01‐DE019638 and R01‐DE021708 to R.M. and B.H.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".