Genetic analysis of hedgehog signaling in ventral body wall development and the onset of omphalocele formation

Daisuke Matsumaru, Ryuma Haraguchi, Shinichi Miyagawa, Jun Motoyama, Naomi Nakagata, Frits Meijlink, Gen Yamada

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)


Background: An omphalocele is one of the major ventral body wall malformations and is characterized by abnormally herniated viscera from the body trunk. It has been frequently found to be associated with other structural malformations, such as genitourinary malformations and digit abnormalities. In spite of its clinical importance, the etiology of omphalocele formation is still controversial. Hedgehog (Hh) signaling is one of the essential growth factor signaling pathways involved in the formation of the limbs and urogenital system. However, the relationship between Hh signaling and ventral body wall formation remains unclear. Methodology/Principal Findings: To gain insight into the roles of Hh signaling in ventral body wall formation and its malformation, we analyzed phenotypes of mouse mutants of Sonic hedgehog (Shh), GLI-Kruppel family member 3 (Gli3) and Aristaless-like homeobox 4 (Alx4). Introduction of additional Alx4Lst mutations into the Gli3Xt/Xt background resulted in various degrees of severe omphalocele and pubic diastasis. In addition, loss of a single Shh allele restored the omphalocele and pubic symphysis of Gli3Xt/+; Alx4Lst/Lst embryos. We also observed ectopic Hh activity in the ventral body wall region of Gli3Xt/Xt embryos. Moreover, tamoxifen-inducible gain-of-function experiments to induce ectopic Hh signaling revealed Hh signal dose-dependent formation of omphaloceles. Conclusions/Significance: We suggest that one of the possible causes of omphalocele and pubic diastasis is ectopicallyinduced Hh signaling. To our knowledge, this would be the first demonstration of the involvement of Hh signaling in ventral body wall malformation and the genetic rescue of omphalocele phenotypes.

Original languageEnglish
Article numbere16260
JournalPloS one
Issue number1
Publication statusPublished - 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General


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