Genetic Analysis of Hedgehog Signaling in Ventral Body Wall Development and the Onset of Omphalocele Formation

BackgroundAn omphalocele is one of the major ventral body wall malformations andis characterized by abnormally herniated viscera from the body trunk. It hasbeen frequently found to be associated with other structural malformations,such as genitourinary malformations and digit abnormalities. In spite of itsclinical importance, the etiology of omphalocele formation is still controversial.Hedgehog (Hh) signaling is one of the essential growth factor signaling pathwaysinvolved in the formation of the limbs and urogenital system. However, therelationship between Hh signaling and ventral body wall formation remainsunclear.
Methodology/Principal FindingsTo gain insight into the roles of Hh signaling in ventral body wall formationand its malformation, we analyzed phenotypes of mouse mutants of Sonichedgehog (Shh), GLI-Kruppel family member3 (Gli3) and Aristaless-like homeobox 4(Alx4). Introduction of additional Alx4Lstmutations into the Gli3Xt/Xt background resultedin various degrees of severe omphalocele and pubic diastasis. In addition,loss of a single Shh allele restored the omphalocele andpubic symphysis of Gli3Xt/+; Alx4Lst/Lstembryos. We also observed ectopic Hh activity in the ventral body wall regionof Gli3Xt/Xt embryos. Moreover, tamoxifen-induciblegain-of-function experiments to induce ectopic Hh signaling revealed Hh signaldose-dependent formation of omphaloceles.
Conclusions/SignificanceWe suggest that one of the possible causes of omphalocele and pubic diastasisis ectopically-induced Hh signaling. To our knowledge, this would be the firstdemonstration of the involvement of Hh signaling in ventral body wall malformationand the genetic rescue of omphalocele phenotypes.