Constitutive Activation of Hedgehog Signaling in FOXD1+ Renal Stromal Cells Impairs Ureteric Epithelial Branching via CXCL12
Bibliographic record
Abstract
Background: Renal dysplasia, characterized by disorganization of stromal tissue, malformation of collecting ducts, and decreased nephron number, is a major cause of renal failure in children. Nephrons and collecting ducts develop via reciprocal inductive interactions between two intermediate mesodermal tissue elements - the Osr1+ metanephric mesenchyme (MM), within which reside Six2+ nephrogenic and Foxd1+ stromal cell progenitors, and the Hoxb7+ ureteric bud, which gives rise to ureteric branches and their daughter collecting ducts. The key roles of expanded Foxd1+ stromal progenitors in the genesis of dysplastic tissue are largely undefined. Here, we identify a novel pathogenic stromal Hh-Cxcl12 signaling axis driving impaired ureteric epithelial branching. Methods: Mice with deficiency of Ptch1 specific to FOXD1+ stromal cells (Foxd1Cre;Ptch1loxP/-; referred to as stromal Ptch1-deficient) were analyzed by immunostaining, single-cell RNA sequencing, and bulk RNA sequencing. To investigate Cxcl12 as a downstream target of increased stromal Hh signaling, in vivo analysis of ureteric branching was assessed in Cxcl12 compound mutants (Foxd1Cre; Ptch1loxP-; Cxcl12loxP/+). Results: Stromal Ptch1-deficient kidneys exhibited renal dysplasia characterized by a 41% reduction in nephron number (P<0.01, n=4) at E18.5 and a 26% reduction in ureteric epithelial branch tips at E12.5 (P<0.01, n=6). Whole kidney qRT-PCR analysis at E13.5 further demonstrated a reduction in ureteric branching effectors Gdnf, Wnt11, Etv4, and Etv5 in stromal Ptch1-deficient mice (P<0.05, n=4). Bulk RNA sequencing of stromal Ptch1-deficient whole kidneys revealed a significant upregulation in numerous medullary stromal markers including the secreted stromal cell-derived factor Cxcl12 (P<0.01, n=3). Complementary single-cell RNA sequencing analysis further demonstrated upregulation of Cxcl12 in medullary stromal clusters of Ptch1-deficient kidneys relative to control samples. Analysis of branching morphogenesis in compound mutant mice heterozygous for Cxcl12 in a stromal Ptch1-deficient background revealed a complete rescue of ureteric epithelial branching defects (P<0.001, n=6). Conclusions: A pathogenic increase in stromal Hh signaling in mice causes nephron deficiency and impaired ureteric epithelial branching due to increased Cxcl12 activation. Funding: Government Support - Non-U.S.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
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".