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

Matsumaru, D. and Haraguchi, R. and Miyagawa, S. and Motoyama, J. and Nakagata, N. and Meijlink, F.C.P.W. and Yamada, G. (2011) Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation. PLoS One, 6, e16260-. ISSN 1932-6203.

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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 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/SIGNIFICANCE: 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. [KEYWORDS: Animals, Dose-Response Relationship, Drug, Embryo, Mammalian, Embryonic Development, Gene Therapy/methods, Hedgehog Proteins/genetics/pharmacology/physiology, Hernia, Umbilical/ etiology/pathology/ therapy, Kruppel-Like Transcription Factors/genetics, Mice, Mice, Mutant Strains, Mutation, Nerve Tissue Proteins/genetics, Phenotype, Pubic Symphysis Diastasis, Signal Transduction]

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:12664
Deposited On:19 Sep 2012 15:36
Last Modified:14 Oct 2012 19:02

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