Mapping the Multi‐Modal Distribution of Craniofacial Phenotypes in NOSIP Mutants
Bibliographic record
Abstract
Nitric Oxide Synthase Interacting Protein (NOSIP) is a E3 mono‐ubiquitin ligase that regulates the activity of protein phosphatase 2A. Deletion of NOSIP leads to severe and variable malformations of the craniofacial complex. Our goal was to use NOSIP mutant mice to understand of mechanisms of phenotypic variation. The phenotype of an individual embryo is the product of the developmental trajectory that it previously traversed. We propose that this concept of canalization is essential for understanding the etiology of complex phenotypic outcomes. We have previously shown that the brain patterns the face, so sequential perturbations affecting the brain and face may create unique developmental trajectories that each embryo transits. We tested this by creating a 3D morphospace of NOSIP heterozygous and homozygous mutants to determine if embryos occupy unique morphospace regions based on affected craniofacial structures. Embryos between embryonic day 10.5 (E10.5) to E17.5 were collected, fixed, and imaged (mCT). Anatomical features were reconstructed using Avizo. NOISP expression appears to be restricted to the neuroepithelium, lower jaw mesenchyme, and mesenchyme and epithelium in tissue adjacent to the frontonasal ectodermal zone between stage E10.5‐11.5. Embryos with a single telencephalic lobe had more severe facial malformations, including micrognathia and obstructed airway without significant changes in early cell apoptosis (via TUNEL staining). Embryos with normal telencephalic vesicle separation had less severe facial phenotypes, including left‐right mild asymmetry and clefting. Overall, it appears that NOSIP‐KO creates a multi‐modal distribution of craniofacial phenotypes along the developmental timeline by affecting early brain development, suggesting that understanding canalization may provide insight into the complexity of genotype‐phenotype map (Fig. ). Support or Funding Information Funding was provided by NIH F32DE08476 and R01DE019638 grants. Schematic of the changing phenotypic landscape describing the multi‐modal distribution of craniofacial phenotypes within NOSIP +/− and NOSIP −/− embryos compared to wildtype (light blue). Figure 1
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".