Investigating the Effects of Frizzed2 Mutations on Craniofacial Skeletal Development
Bibliographic record
Abstract
During early embryonic development cells that form different organs such as the face, limbs, heart are unspecified. Cell‐to‐cell communication using various signalling mechanisms supports development of tissues and organs. My project concentrates on understanding cell signalling pathway involving Wingless‐related proteins (WNTs) and their role in embryonic bone and cartilage development. There is a human genetic disease caused by mutations in eight WNT pathway genes called Robinow Syndrome (RS). The functional impacts of these gene mutations on skeletogenesis remain unexplored. RS patients present with facial abnormalities and short stature. The objective of my project is to investigate the functional impacts of Frizzled2 ( FZD2 ), one class of receptor that binds to WNTs, on facial skeletal development using the chicken embryo model. There are two FZD2 variants and that cause RS, one in the extracellular ligand binding domain ( FZD2 P142L ) and the other in the intracellular domain( FZD2 G434V ). We are using the chicken since early facial and limb morphogenesis is conserved with humans. Additionally, local transgenesis is possible. We hypothesize that the FZD2 P142L variant will cause abnormal ligand‐receptor binding or receptor dimerization and the FZD2 G434V variant will interfere with Dishevelled recruitment thus altering signal transduction. We used avian replication‐competent retroviruses containing human FZD2 genes or the GFP control virus. Virus was added to high density micromass cultures composed of frontonasal mass mesenchymal cells and were assessed for differentiation after 4, 6 and 8 days of culture. All cultures formed cartilage and started to mineralize as shown by Alcian blue and alkaline phosphatase staining. However, the amount of cartilage significantly decreased by 8 days for all viruses (between 35‐53%). AlkPO staining increased in the GFP cultures but was significantly decreased by all FZD2 viruses. At 4 days, the FZD2 viruses increased cartilage condensations compared to GFP. However, at 6 days all viruses were equivalent in terms of proportion of cartilage in the cultures. By 8 days the trend had reversed and the FZD2 viruses significantly decreased chondrogenesis. We conclude that the three viruses wtFZD2 and the two variants are equivalent in their effects, initially stimulating and then inhibiting chondrogenesis. This indicates that the variants are still active rather than causing a complete loss‐of‐function. It is also possible that the variants are causing a gain‐of‐function since they behave similarly to over‐expression of wtFZD2 . This project will help unravel the complex mechanisms underpinning skeletal dysplasias affecting the face and other organs such as the limbs due to the common molecular markers and transcription factors.
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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) | 0.002 | 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".