Upstream Enhancer Elements of Shh Regulate Oral and Dental Patterning
Upstream Enhancer Elements of Shh Regulate Oral and Dental Patterning
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DOI：
10.1177/0022034518758642
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发表时间：
2018-08-01
影响因子：
7.6
通讯作者：
Shiroishi, T.
中科院分区：
文献类型：
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作者：
Seo, H.;Amano, T.;Shiroishi, T.
Sonic Hedgehog(Shh)在发育过程中对图案的形成起着重要作用。ShH转录是由一个包含大量增强子的长程调控机制调控的，这些增强子分布在小鼠基因组中近850 kb的范围内。神经系统中的Shh增强子在内含子和Shh上游的430kb之间被发现。在Shh上游的610kb至850kb之间的口腔、咽、肺、肠道和四肢中发现了增强剂。然而，Shh上游430~610kb的基因间隔区仍有待阐明。在本研究中，我们发现了一个位于Shh上游558kb的新型长程增强子。该增强剂在口腔和胡须中具有体内活性。口腔中已知Shh的增强子-哺乳动物爬行动物保守序列1(MRCS1)的靶向缺失导致了额外磨牙的形成，证实了该基因间隔区在牙齿Shh转录中的重要作用。此外，我们阐明了Lef1/TCFs与新的增强子和MRCS1的结合，表明Wnt/β-catenin信号通过这些增强子调节口腔中的Shh信号。
Sonic hedgehog (Shh) is important in pattern formation during development. Shh transcription is modulated by a long-range regulatory mechanism containing a number of enhancers, which are spread over nearly 850 kb in the mouse genome. Shh enhancers in the nervous system have been found between intron and 430 kb upstream of Shh. Enhancers in the oral cavity, pharynx, lung, gut, and limbs have been discovered between 610 kb and 850 kb upstream of Shh. However, the intergenic region ranging from 430 to 610 kb upstream of Shh remains to be elucidated. In the present study, we found a novel long-range enhancer located 558 kb upstream of Shh. The enhancer showed in vivo activity in oral cavity and whiskers. A targeted deletion from the novel enhancer to mammal reptile conserved sequence 1 (MRCS1), which is a known enhancer of Shh in oral cavity, resulted in supernumerary molar formation, confirming the essential role of this intergenic region for Shh transcription in teeth. Furthermore, we clarified the binding of Lef1/Tcfs to the new enhancer and MRCS1, suggesting that Wnt/beta-catenin signaling regulates Shh signaling in the oral cavity via these enhancers.