1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan [3] Department of Molecular Pathology, Ehime University Graduate School of Medicine, Ehime, Japan.
Eur J Hum Genet. 2014 Mar;22(3):350-7. doi: 10.1038/ejhg.2013.160. Epub 2013 Aug 14.
Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4Lst) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the development of the genital tubercle (GT) and its derivatives, the external genitalia, is affected by this mutation. We thus performed genetic and tissue labeling analyses in mutant mice. Alx4Lst/Lst mutants displayed hypoplasia of the dorsal GT and reduced expression of Fibronectin. We analyzed cell migration during GT formation by tissue labeling experiments and discovered that the cells located in the proximal segment of the umbilical cord (infra-umbilical mesenchyme) migrate toward the dorsal part of the GT. The Alx4Lst/Lst mutants also displayed augmented expression of Hh signal-related genes. Hence, we analyzed a series of combinatorial mutants for Alx4, Sonic hedgehog (Shh) and GLI-Kruppel family member 3 (Gli3). These phenotype-genotype analyses suggested a genetic interaction between Alx4 and Hh signaling during GT formation. Moreover, Hh gain-of-function mutants phenocopied some of these phenotypes. These observations reveal novel information regarding the pathogenic mechanisms of syndromic lower ventral body malformations, which are largely unknown.
虽然有几种综合征包括腹部体壁和外部生殖器的异常，但这种相关性的发育基础在很大程度上尚不清楚。Aristaless-like 4（Alx4，Strong 的 luxoid：Alx4Lst）中的自然发生突变具有腹部体壁和骨盆带异常。我们试图确定这种突变是否会影响生殖器结节（GT）及其衍生物外部生殖器的发育。因此，我们在突变小鼠中进行了遗传和组织标记分析。Alx4Lst/Lst 突变体显示背侧 GT 发育不良和纤维连接蛋白表达减少。我们通过组织标记实验分析了 GT 形成过程中的细胞迁移，并发现位于脐带近端（脐下间充质）的细胞向 GT 的背侧迁移。Alx4Lst/Lst 突变体还表现出 HH 信号相关基因的表达增强。因此，我们分析了一系列具有 Alx4、Sonic hedgehog（Shh）和 GLI-Kruppel 家族成员 3（Gli3）的组合突变体。这些表型-基因型分析表明在 GT 形成过程中 Alx4 和 HH 信号之间存在遗传相互作用。此外，HH 功能获得性突变体模拟了其中一些表型。这些观察结果揭示了综合征性下腹部畸形的发病机制的新信息，而这些信息在很大程度上尚不清楚。
