title: Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation.
abstract: 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.
  
  
  RESULTS
  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 Alx4(Lst) mutations into the Gli3(Xt/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 Gli3(Xt/+); Alx4(Lst/Lst) embryos. We also observed ectopic Hh activity in the ventral body wall region of Gli3(Xt/Xt) embryos. Moreover, tamoxifen-inducible gain-of-function experiments to induce ectopic Hh signaling revealed Hh signal dose-dependent formation of omphaloceles.
  
  
  CONCLUSIONS
  We suggest that one of the possible causes of omphalocele and pubic diastasis is ectopically-induced 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.
authors.affiliation: Global COE, Cell Fate Regulation Research and Education Unit, Department of Organ Formation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsumaru
authors.forename: Ryuma
authors.initials: R
authors.lastname: Haraguchi
authors.forename: Shinichi
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Jun
authors.initials: J
authors.lastname: Motoyama
authors.forename: Naomi
authors.initials: N
authors.lastname: Nakagata
authors.forename: Frits
authors.initials: F
authors.lastname: Meijlink
authors.forename: Gen
authors.initials: G
authors.lastname: Yamada
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D047108:Embryonic Development; D015316:Genetic Therapy / Q000379:methods; D053823:Hedgehog Proteins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D006554:Hernia, Umbilical / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D046548:Pubic Symphysis Diastasis; D015398:Signal Transduction; D000074290:Zinc Finger Protein Gli3
chemical_list: C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3