TGFβ Signaling Regulates Renal Patterning via Cadm1 During Nephrogenesis
Bibliographic record
Abstract
Background: Impaired nephrogenesis affects kidney health, causing childhood CKD and increasing CKD risk in adults. Foxd1+ kidney stromal cells regulate nephron development by interacting with Six2+ nephrogenic precursors. Previously, we (Rowan CJ et al, Development, 2018) demonstrated that Hedgehog-GLI signaling in Foxd1+ stromal cells is required to promote murine nephrogenesis through TGFβ signaling, specifically via promoting the transformation of mesenchymal cells into epithelial cells (MET) in the Six2+ nephrogenic zone. However, the underlying molecular mechanisms that guide MET are incompletely defined. Here we aim to define molecular mechanisms by which TGFβ signaling regulates nephrogenesis. Methods: Whole-kidney RNA seq and single-cell RNA seq to examine Tgfβr2 deficiency in Foxd1+ stromal and Six2+ nephrogenic kidneys. We validated the bioinfrmatics data through immuno-staining and Western blot. Compound mutant mice were generated to investigate the deficiency of Cadm1 alone or both Tgfβr2 and Cadm1, followed by histological analysis, immunostaining, and nephron quantitation. Results: Whole-kidney RNA seq (n=4) and scRNA seq (n=169 cell, P<0.001) in Foxd1+ stromal and Six2+ nephrogenic Tgfβr2-deficient kidneys identified Cadm1 (P<0.00003,P<0.0013) in Foxd1+stromal cells as a TGFβ signaling downstream target. Western blot analysis in HEK-T293 cells (n=2) demonstrated that treatment with TGFβ1 induced CADM1 expression in a dose-dependent manner. Kidney tissue with Stromal and/or nephrogenic cell deficiency of Cadm1 exhibited normal nephrogenesis (n=2-3,P<0.01). Kidney tissue with deficiency of both Tgfβr2 and Cadm1 in Foxd1+ stroma exhibited renal hypodysplasia characterized by 32% reduction in kidney:body weight (n=6,P<0.0001), a 35% reduction in nephron number (n=3,P<0.05), expansion of Six2+ cells/UB tip (n=2,P<0.05), and loosely packed cortex and irregular stromal pattern (n=3). Similarly, kidney tissue with deficiency of both Tgfβr2 and Cadm1 in Six2+ nephrogenic cells exhibited renal hypodysplasia characterized by a 27% reduction in kidney:body weight (n=3,P<0.01), a 48% reduction in nephron number (n=2,P<0.05) and expansion of Six2+ cells/UB tip (n=3, P<0.01). Conclusions: We conclude that Cadm1 is required for normal nephrogenesis in mice. Further, our data suggest that CADM1 may play a role in regulating the epithelialization of nephrogenic precursors under the influence of TGFβ signaling 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".