New mouse models of congenital anorectal malformations

J Pediatr Surg. 2000 Feb;35(2):227-30; discussion 230-1. doi: 10.1016/s0022-3468(00)90014-9.


Background/purpose: The genetic, embryological, and pathogenetic aspects of hindgut development remain poorly understood. Recently, the morphogenetic pathway involving the Sonic hedgehog (Shh) gene has been shown essential to the normal development of many midaxial organs, including the foregut. This study reports genetically based murine models of congenital anorectal malformations (CAM) involving the Shh-responsive transcription factors, Gli2 and Gli3. Its purpose is to show the necessity of these 2 factors to normal hindgut development.

Methods: Gli2-/- mutants were generated by a targeted deletion. Gli3-/- mutants are spontaneous mutants involving the Gli3 gene. Gli2-/- Gli3+/- mutants were generated by intercrossing double heterozygotes. Whole-mount midsagittal sections of the embryos were analyzed on embryonic days (E) 11.5 and E13.5.

Results: Gli3-/- mutants had anal stenosis and ectopic anus, and Gli2-/- mutants showed imperforate anus and rectourethral fistula. Gli2-/- Gli3+/- mutants had a cloacal abnormality.

Conclusions: The phenotypic abnormalities observed in these mutant mice are identical to the spectrum of human CAM. The severity of the phenotype appears to reflect the gene dose. Gli2 and Gli3 play an important role in the normal development of murine hindgut. The results of this study provide, for the first time, a molecular basis for CAM.

MeSH terms

  • Anal Canal / abnormalities
  • Animals
  • Cell Division
  • Cloaca / embryology
  • Disease Models, Animal*
  • Endoderm / cytology
  • Gene Expression Regulation, Developmental*
  • Mice
  • Mice, Mutant Strains
  • Phenotype
  • Rectum / abnormalities*
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • Transcription Factors