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

Abstract

BackgroundAn 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 FindingsTo 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/SignificanceWe 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.

Multiple abnormalities due to a nonsense mutation in the Alx4 gene

“…The frequency of this malformation is reported to be approximately 1 in 4000 live births (Matsumaru et al, 2011), and despite this high incidence, the cause of omphalocele formation remains unclear. In addition to ).…”

Pathogenesis of bladder exstrophy: A new hypothesis

“…Concordant recovery of the physiological umbilical hernia and the closure of pelvic girdle has been reported in genetically modified mice [23].…”

“…Concordant recovery of the physiological umbilical hernia and closure of the pelvic girdle in genetically modified mice have been demonstrated by Matsumaru et al [23], and Cheng et al [26], established a genetic model of BEEC in p63-/-knockout mice, which showed the complete spectrum of BEEC in association with exomphalus. These studies, as well as the frequent occurrence of BEEC (especially cloacal exstrophy) with exomphalus, suggest that body wall closure and closure of the pubic arch may be interrelated.…”

Epispadias and the associated embryopathies: genetic and developmental basis

“…However, little information has been revealed for such caudal body formation. Genetic studies identified a few genes for the formation of the dorsal part of GT and the ventral body wall (34). Some of these genes are initially expressed in the mesenchyme adjacent to the umbilical cord.…”