Implication of Wt1 in the pathogenesis of nephrogenic failure in a mouse model of retinoic acid-induced caudal regression syndrome

Herman K W Tse, Maran B W Leung, Adrian S Woolf, Aswin L Menke, Nicholas D Hastie, John A Gosling, Chi-Pui Pang, Alisa S W Shum

Research output: Contribution to journalArticlepeer-review

Abstract

Renal malformations are common human birth defects that sometimes occur in the context of the caudal regression syndrome. Here, we found that exposure of pregnant mice to all-trans retinoic acid, at a time when the metanephros has yet to form, causes a failure of kidney development along with caudal regression. Maternal treatment with Am580 (retinoic acid receptor alpha agonist) also induced similar patterns of kidney maldevelopment in the fetus. In metanephroi from retinoic acid-treated pregnancies, renal mesenchyme condensed around the ureteric bud but then failed to differentiate into nephrons, instead undergoing involution by fulminant apoptosis to produce a renal agenesis phenotype. Results of whole organ cultures in serum-free medium, and also tissue recombination experiments, showed that the nephrogenic defect was intrinsic to the kidney and that it resided in the metanephric mesenchyme and not the ureteric bud. Renal mesenchyme from control embryos expressed Wilms' tumor 1 (Wt1), but this transcription factor, which is indispensable for kidney development, failed to express in metanephroi of retinoic acid-exposed embryos. Wt1 expression and organogenesis were both restored, however, when metanephroi from retinoic acid-treated pregnancies were grown in serum-containing media. Our data illuminate the pathobiology of a severe, teratogen-induced kidney malformation.
Original languageEnglish
Pages (from-to)1295-307
Number of pages13
JournalThe American Journal of Pathology
Volume166
Issue number5
DOIs
Publication statusPublished - May 2005

Keywords

  • Abnormalities, Multiple
  • Anal Canal
  • Animals
  • Coculture Techniques
  • Congenital Abnormalities
  • Embryonic Development
  • Female
  • Gene Expression
  • Genes, Wilms Tumor
  • Kidney
  • Lumbar Vertebrae
  • Mesoderm
  • Mice
  • Mice, Inbred ICR
  • Spinal Cord
  • Syndrome
  • Tissue Culture Techniques
  • Tretinoin

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