Interaction between the epithelium and mesenchyme coordinates patterning and differentiation of oral cavity structures including teeth, palatal rugae and tongue papillae. SHH is one of the key signaling molecules for this interaction. Epithelial expression of Shh in the tooth buds and tongue papillae is regulated by at least two enhancers, MRCS1 and MFCS4. However, it is unclear how the two enhancers cooperate to regulate Shh. Here, we found that simultaneous deletion of MRCS1 and MFCS4 results in the formation of a supernumerary tooth in front of the first molar. Since deletion of either single enhancer barely affects tooth development, MRCS1 and MFCS4 evidently act in a redundant fashion. Binding motifs for WNT signaling mediators are shared by MRCS1 and MFCS4, and play a central role in regulating Shh expression, indicating that the two redundant enhancers additively exert their Shh regulation by responding to WNT signal input.
Bibliographical noteFunding Information:
We thank Y. Mizushina for generating the double KO mouse of MRCS1 and MFCS4. We thank H. Nakazawa for generating transgenic mice. We thank Dr. T. Takada and Dr. K. Sumiyama for helpful genomic analysis and discussion. We thank Dr. P. Beachy for the Shh KO mouse strain and Dr. A. McMahon for the Shh probe. This study was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
© 2017 The Author(s).
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