Murine models of VACTERL syndrome: Role of sonic hedgehog signaling pathway

Background/Purpose: VACTERL syndrome is a common surgical condition affecting the development of many midaxial organs. The etiology, embryology, and pathogenesis of the VACTERL syndrome are not known. The authors report here new mouse models of VACTERL syndrome involving the Sonic hedgehog (Shh) signaling, pathway. Methods: Mutant mice involving Shh signaling, the Shh transcription factors Gli2-/- and Gli3-/-, Gli2-/-;Gli3+/double heterozygotes, and Shh-/- were analyzed. Results: In addition to reported vertebral, anal, tracheoesophageal, and limb anomalies, mutant mice display cardiac, renal, and associated anomalies, namely congenital diaphragmatic hernia and omphalocele, known to be associated in VACTERL syndrome. The Shh transcription factors Gli2 and Gli3 have specific and overlapping roles in the induction of VACTERL phenotypes in a gene-dose-dependent manner in these mutants. Conclusion: To the authors' knowledge, these mutant mice represent the first animal model that mimics the human VACTERL syndrome, and suggests that aberrations in Shh signaling might be involved in the VACTERL syndrome.