Indian Hedgehog Signalling in Kidney Development
Bibliographic record
Abstract
Background: Hedgehog (Hh) signalling is critical in the development of the kidney, with genetic alterations of Hh pathway components leading to defects in nephron formation. Indian hedgehog (Ihh) is one of three ligands that activate the Hh pathway, however the cellular sources and functional role of Ihh in kidney development is not well understood. Methods: We utilised a novel 3D imaging technique, combining wholemount fluorescence in situ hybridisation, immunolabelling and optical clearing to visualise Ihh mRNA localisation in 3D in the developing mouse embryonic kidney at cellular resolution. Furthermore, we have utilised a total Ihh knockout mouse model and Cre recombinase-based techniques to conditionally delete Ihh in the intermediate mesoderm, using the inducible Osr1-CreERT2, to begin to interrogate the functional role of Ihh in the developing kidney. Results: Ihh mRNA was detected in the developing mouse kidney from embryonic day (E)16.5; during the maturation of tubules and glomeruli and maintained at E18.5 and the first day postnatally. Double labelling with Lotus tetragonolobus lectin revealed that Ihh primarily localised to the proximal tubule. As Ihh is detected as the mature nephron is developing, we hypothesise that Ihh will be important in nephrogenic development. We observed that Ihh-/- kidneys are smaller at E16.5 with some observed displaying highly disorganised, abnormal morphology. Additionally, Ihh-/- kidneys have a significantly reduced total glomerular number (p=0.0297) and a reduction in SIX2+ nephron precursor cells in around 40% of Ihh-/- kidneys compared with wild-type littermates, overall suggesting defects in kidney development in Ihh-/- mice. Conditional deletion of Ihh in the Osr1+ intermediate mesoderm, results in a significantly decreased kidney/bodyweight ratio at E18.5 (p=0.0089), providing initial evidence of an importance for Ihh in intermediate mesoderm derived cells in the development of the kidney. Conclusions: In summary, using a novel imaging technique we identified the onset of Ihh expression in maturing proximal tubules of the mouse embryonic kidney. Further, we observed defects in the development of Ihh total knockout kidneys and initial data indicates a function for Ihh in intermediate mesoderm derived cells.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".