Global COE, Cell Fate Regulation Research and Education Unit, Department of Organ Formation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
PLoS One. 2011 Jan 20;6(1):e16260. doi: 10.1371/journal.pone.0016260.
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.
脐膨出是一种主要的腹侧体壁畸形，其特征是内脏异常从体干疝出。它经常与其他结构畸形有关，如泌尿生殖系统畸形和指（趾）畸形。尽管其具有临床重要性，但脐膨出的发生机制仍存在争议。Hedgehog（Hh）信号是参与肢体和泌尿生殖系统形成的必需生长因子信号通路之一。然而，Hh 信号与腹侧体壁形成之间的关系尚不清楚。
方法/主要发现：为了深入了解 Hh 信号在腹侧体壁形成及其畸形中的作用，我们分析了 Sonic hedgehog（Shh）、GLI-Kruppel 家族成员 3（Gli3）和 Aristaless-like homeobox 4（Alx4）的小鼠突变体的表型。在 Gli3(Xt/Xt)背景下引入额外的 Alx4(Lst)突变导致各种程度的严重脐膨出和耻骨分离。此外，单个 Shh 等位基因的缺失恢复了 Gli3(Xt/+)；Alx4(Lst/Lst)胚胎的脐膨出和耻骨联合。我们还观察到 Gli3(Xt/Xt)胚胎腹侧体壁区域存在异位 Hh 活性。此外，用他莫昔芬诱导的异位 Hh 信号的功能获得实验揭示了 Hh 信号剂量依赖性的脐膨出形成。
结论/意义：我们认为脐膨出和耻骨分离的一个可能原因是异位诱导的 Hh 信号。据我们所知，这将是首次证明 Hh 信号参与腹侧体壁畸形和遗传拯救脐膨出表型。
