Tsukiji Nagaharu, Amano Takanori, Shiroishi Toshihiko
Department of Clinical and Laboratory Medicine, Faculty of Medicine, University of Yamanashi, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
Mammalian Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-8540, Japan.
Mech Dev. 2014 Feb;131:127-36. doi: 10.1016/j.mod.2013.09.003. Epub 2013 Oct 22.
Hedgehog (Hh) signaling plays pivotal roles in morphogenesis of several embryonic tissues, including the primitive gut. In the mouse embryo, Sonic hedgehog (Shh) is expressed in endodermal epithelia from the oral cavity to the intestine, and contributes to cell proliferation in the underlying mesenchyme and subsequent differentiation into the gastrointestinal smooth muscle. Three evolutionary conserved non-coding sequences in the region upstream of the Shh coding sequence contain endoderm-specific enhancers for Shh expression. Although Shh expression in the endodermal epithelial lining is mostly attributed to these three enhancers, none of them regulates gene expression in the gastroesophageal epithelium. Here, we found that a 1.7Kb fragment located 100Kb upstream of the Shh coding sequence contains a functional element for Shh expression in endodermal organs, including the esophagus and stomach. Compared with the three known endodermal enhancers, this novel enhancer shows less evolutionary conservation, even among rodents. In mouse embryonic endodermal tissues, the seamless expression of Shh is achieved by a patchwork of multiple enhancers with different rates of evolution.
刺猬信号通路（Hh）在包括原始肠道在内的多种胚胎组织的形态发生过程中发挥着关键作用。在小鼠胚胎中，音猬因子（Shh）在从口腔到肠道的内胚层上皮中表达，并促进其下方间充质中的细胞增殖以及随后分化为胃肠道平滑肌。Shh编码序列上游区域的三个进化保守非编码序列包含Shh表达的内胚层特异性增强子。尽管内胚层上皮衬里中的Shh表达主要归因于这三个增强子，但它们均不调节胃食管上皮中的基因表达。在此，我们发现位于Shh编码序列上游100Kb处的一个1.7Kb片段包含一个在内胚层器官（包括食管和胃）中Shh表达的功能元件。与三个已知的内胚层增强子相比，这个新的增强子在进化上的保守性较低，即使在啮齿动物中也是如此。在小鼠胚胎内胚层组织中，Shh的无缝表达是通过多个具有不同进化速率的增强子拼凑实现的。
