Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation.
Genetic analysis of Hedgehog signaling in ventral body wall development and the onset of omphalocele formation.
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DOI：
10.1371/journal.pone.0016260
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发表时间：
2011-01-20
期刊：
影响因子：
3.7
通讯作者：
Yamada G
中科院分区：
文献类型：
--
作者：
Matsumaru D;Haraguchi R;Miyagawa S;Motoyama J;Nakagata N;Meijlink F;Yamada G
脐膨出是一种主要的腹侧体壁畸形，其特征是内脏从躯干异常突出。它经常被发现与其他结构畸形，如泌尿生殖系统畸形和手指畸形。尽管脐膨出的临床重要性，但其病因仍有争议。Hedgehog（Hh）信号通路是参与四肢和泌尿生殖系统形成的重要生长因子信号通路之一。然而，Hh信号和腹体壁形成之间的关系仍然不清楚。为了深入了解Hh信号在腹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（Gli 3）和Aristaless-like homeobox 4（Alx 4）小鼠突变体的表型。在Gli 3Xt/Xt背景中引入额外的Alx 4Lst突变导致不同程度的严重脐膨出和耻骨膨出。此外，单个Shh等位基因的丢失恢复了Gli 3Xt/+; Alx 4Lst/Lst胚胎的脐膨出和耻骨联合。我们还观察到异位Hh活性在腹体壁区域的Gli 3Xt/Xt胚胎。此外，他莫昔芬诱导的功能获得性实验，以诱导异位Hh信号显示Hh信号剂量依赖性脐膨出的形成。我们认为脐膨出和耻骨膨出的可能原因之一是异位诱导的Hh信号。据我们所知，这将是第一次证明Hh信号参与腹体壁畸形和脐膨出表型的遗传拯救。
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. 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. 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.
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DOI：
10.1006/bbrc.1997.7124
发表时间：
1997-08-28
影响因子：
3.1
作者：
Feil, R;Wagner, J;Chambon, P
通讯作者：
Chambon, P
DOI：
10.1073/pnas.93.20.10887
发表时间：
1996-10-01
影响因子：
11.1
作者：
Feil, R;Brocard, J;Chambon, P
通讯作者：
Chambon, P
影响因子：
3.5
作者：
Brugmann, Samantha A.;Allen, Nancy C.;Helms, Jill A.
通讯作者：
Helms, Jill A.
影响因子：
2.7
作者：
Brewer, S;Williams, T
通讯作者：
Williams, T
影响因子：
4.6
作者：
Butterfield, Natalie C.;Metzis, Vicki;Wicking, Carol
通讯作者：
Wicking, Carol