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/β-catenin signaling regulates Shh signaling in the oral cavity via these enhancers.
Bibliographical noteFunding Information:
We thank H. Nakazawa for support in generating PCS1–MRCS1Δ/Δ mice. This work was supported by the National Research Foundation (NRF), funded by the Korean government (MEST) (NRF-2013R1A1A2013200) and in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS-24247002). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.
© International & American Associations for Dental Research 2018.
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