Draft 39

MSX2 inhibits the promoter sequence of amelogenin, antagonizing downstream C/EBPα as well as DLX2. This pathway is illustrated in figure 1. In the heterozygous mutant, decreased transcriptional repressor activity of MSX2 ultimately results in increased amelogenin expression.² This increase of expressed amelogenin in the developing tooth ultimately results in increased enamel thickness, as well as increased rod size.² In figure 2, Molla et al. analyzed 3 month postnatal mice with the wild type, heterozygous, and homozygous mutations. Molla et al. measured a 1.3-fold increase in enamel thickness² in Msx2^+/- mutants compared to the wild type. Of course, this Msx2^+/– mutation is not a reliably heritable trait, and therefore a consistent observation of this phenotype among Homo Lontra populations must be the result of a cis-regulatory mutation, specifically within MSX2 enhancers. MSX2 contains a BMP-responsive enhancer sequence³, and a subsequent mutation within this enhancer sequence in Homo Lontra was found to result in the similar phenotype to Msx2^+/– mutants.

1. Li, J., Parada, C., & Chai, Y. (2017). Cellular and molecular mechanisms of tooth root development. Development, 144(3), 374–384. doi: 10.1242/dev.137216
2. Molla, M., Descroix, V., Aïoub, M., Simon, S., Castañeda, B., Hotton, D., … Berdal, A. (2010). Enamel Protein Regulation and Dental and Periodontal Physiopathology in Msx2 Mutant Mice. The American Journal of Pathology, 177(5), 2516–2526. doi: 10.2353/ajpath.2010.091224
3. Brugger, S. M., Merrill, A., Torres-Vazquez, J., Wu, N., Ting, M., Cho, J., … Maxson, R. (2004). A phylogenetically conserved cis-regulatory module in the Msx2 promoter is sufficient for BMP-dependent transcription in murine and Drosophila embryos. Development, 131(20), 5153–5165. doi: 10.1242/dev.01390