Loss of Slit2 in the PAX2+ Progenitor Cells Causes the Congenital Anomalies of the Kidney and Urinary Tract Phenotype in Mice
Bibliographic record
Abstract
Background: Congenital anomalies of the kidney and urinary tract (CAKUT) account for 2-3% of all birth defects and are a major cause of chronic kidney disease (CKD) and kidney failure in children and young adults under 40 years old. Despite the high incidence of CKD in children with CAKUT, the pathogenesis of CAKUT remains largely unclear. SLIT2 and ROBO2 play essential roles in ureteric bud outgrowth, kidney and urinary tract development, and mutations in either SLIT2 or ROBO2 have been identified in CAKUT patients. However, the cell-specific roles of SLIT2 and ROBO2 during kidney and urinary tract development, as well as the pathogenesis of CAKUT, are not well understood. Methods: We performed immunostaining analysis of SLIT2/ROBO2 protein expression in the developing mouse kidney and ureter. We generated Slit2 and Robo2 conditional knockout mice using Pax2-Cre, which is expressed in the early nephrogenic zone, including the ureteric bud and cap mesenchyme (i.e., Slit2flox/flox;Pax2-Cre+ or Slit2 cKO, and Robo2flox/flox;Pax2-Cre+ or Robo2 cKO). We analyzed the kidney and urinary tract phenotypes in Slit2 cKO and Robo2 cKO mice and their wild-type littermate by gross and histological examinations. Cellular and molecular phenotypes of the urothelial and ureteral mesenchyme were studied using cell-specific markers. Results: We found that SLIT2 and ROBO2 are expressed in the early nephrogenic zone. Deletion of Slit2 using Pax2Cre leads to hydronephrosis and early mortality after birth. However, deletion of Robo2 using Pax2Cre has no discernible CAKUT phenotype in mice. At the histological level, Slit2 cKO mice develop a duplex kidney, hydroureter, and hydronephrosis, accompanied by a low nephron number at birth. Cell-specific marker analysis showed that Slit2 cKO mice did not develop normal urothelial and ureteral smooth muscle cells at E14.5 and P0. Conclusion: Our results demonstrate that SLIT2, but not ROBO2, is essential for the development of PAX2+ progenitor cells. Loss of SLIT2 in PAX2+ progenitor cells leads to a CAKUT and obstructive uropathy phenotype in mice. Funding: NIDDK Support, Other U.S. Government Support
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".