CXCL12 and WNT5A Control Nephron Number in the Normal and Hypodysplastic Kidney
Bibliographic record
Abstract
Background: Renal hypodysplasia, defined by abnormally small kidneys with low nephron number and expanded stromal tissue, is the major cause of childhood renal failure. While molecular mechanisms controlling nephrogenesis have been elucidated, factors that control the number of nephrons is largely unknown and important as low nephron number is critical to kidney function in childhood and as an antecedent cause of adult-onset kidney and cardiovascular disease. Nephrons and stromal cells arise during embryonic development from Osr1-derived Six2+ and Foxd1+ progenitors, respectively. Previous work demonstrated that increased Hedgehog (Hh) signaling in Osr1+ kidney progenitor cells disrupts normal stromal patterning (Sheybani et al., 2018). Here, we investigate the functional contribution of the embryonic renal stroma in determining nephron number. Methods: Constitutive active Hh signaling in Foxd1+ stromal cells was generated by deletion of Ptch1, a Hh cell surface receptor, in a Cre-dependent manner. Compound mutant mice with Foxd1Cre-dependent deficiency of Cxcl12 or Wnt5a together with Ptch1, and mice with Foxd1Cre-dependent deletion of Cxcl12, were generated. Kidney tissue was analyzed by histology, single-cell (sc) and bulk RNA sequencing. Results: Stromal Ptch1-deficient kidneys exhibited renal hypodysplasia characterized by a 41% reduction in nephron number (P<0.01,n=4) and expansion of Foxd1-derived PDGFRB+ medullary stromal cells at E18.5. Complementary scRNA-seq and bulk RNA sequencing (n=3) identified increased expression of medullary stromal Cxcl12 (P<0.001) and Wnt5a (P<0.01) ligands. Foxd1Cre-dependent deficiency of Cxcl12 or Wnt5a together with Ptch1 rescued nephron number by 32% (P<0.001,n=4) or 31% (P<0.05,n=3), respectfully. Analysis of stromal Cxcl12-deficient kidneys demonstrated renal hypoplasia characterized by a 28% reduction in nephron number (P<0.01,n=4) at P4 due to impaired nephron epithelialization. Bulk RNA sequencing of stromal Cxcl12-deficient kidneys (n=3) showed dysregulation of genes associated with retinoic acid signaling, such as Crabp1/2 (P<0.01) and Aldh1a2 (P<0.05), and genes associated with Hippo signaling, such as Cdc42 (P<0.05) and Taz (P<0.05). Conclusions: Increased stromal Cxcl12 and Wnt5a signal non-autonomously to drive low nephron number in renal hypodysplasia. Stromal Cxcl12 functions physiologically to regulate nephron number. 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 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".