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

Background/Purpose: VACTERL syndrome is a common surgical condition affecti ng the development of many midaxial organs. The etiology, embryology, and p athogenesis of the VACTERL syndrome are not known. The authors report here new mouse models of VACTERL syndrome involving the Sonic hedgehog (Shh) sig naling 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 li mb anomalies, mutant mice display cardiac, renal, and associated anomalies, namely congenital diaphragmatic hernia and omphalocele, known to be associ ated 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 firs t animal model that mimics the human VACTERL syndrome, and suggests that ab errations in Shh signaling might be involved in the VACTERL syndrome. Copyr ight (C) 2001 by W.B. Saunders Company.