The CPLANE Protein Fuzzy Regulates Primary Ciliogenesis Through Actin Remodeling
Bibliographic record
Abstract
Background: Defects in primary cilia cause a set of diseases termed ciliopathies manifesting in developmental defects including cystic/dysplastic kidneys. Mutations in ciliogenesis and planar cell polarity (CPLANE) genes FUZZY, INTURNED, and WDPCP lead to a ciliopathy spectrum with abnormal kidney phenotypes. Although Fuzzy ortholog in D.Melanogaster was identified as a part of the planar cell polarity and actin regulatory pathway, its functions in primary cilia assembly and ciliopathies remain largely unknown. We hypothesize that Fuzzy modulates actin-assembly involved in primary cilia formation. Methods: The interactions between Fuzzy-Flag, p190A RhoGAP and IQGAP1-GFP were assessed by co-Immunoprecipitation. Rhotekin G protein-binding domain-eGFP biosensor in mutant and control mouse embryonic fibroblast (MEF) cells was used to measure RhoA activity. IQGAP1 was knocked down by siRNA in Retinal Pigmented Epithelial cells (RPE-1). Overexpression of Fuzzy-GFP was done by stable transfection in MDCK cells. Immunofluorescence with gamma-tubulin, Arl13b and phalloidin was used for cilia assessment. Results: We established that Fuzzy interacts with p190A RhoGAP and controls its localization to the basal body. Normally, p190ARhoAGAP localizes to the primary cilia base and inactivates the actin-regulating protein RhoA. However, in Fuzzy mutant cells, RhoA is excessively activated. We also demonstrate that Fuzzy interacts with IQGAP1 - a protein that facilitates the interaction between p190ARhoGAP and RhoA. siRNA-mediated knockdown of IQGAP1 negatively affected ciliogenesis in RPE-1 cells. On the other hand, we show that Fuzzy is involved in regulation of the early stages of ciliogenesis: the overexpression of Fuzzy in MDCK cells triggered earlier cortical actin clearing at the apical membrane and earlier ciliogenesis. Conclusions: We conclude that Fuzzy regulates the actin cytoskeleton at the primary cilium during the early and later stages of ciliogenesis. Fuzzy recruits p190A RhoGAP to the ciliary base and interacts with IQGAP1 resulting in the inhibition of RhoA and the suppression of excessive actin polymerization at the base of the cilium. Fuzzy is also involved in the process of actin clearing during the early stages of ciliogenesis, but the exact mechanism is yet to be elucidated. Funding: Government Support - Non-U.S.
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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".