By the cap stage, these knots are fully developed and have begun to serve as central regulators of tooth development by secreting signaling factors from the BMP, FGF, Shh, and Wnt families [Thesleff and Sharpe, 1997].
As the epithelium thickens, it will activate the mesenchyme, which, during the cap stage, will induce adjacent epithelium to differentiate into the enamel organ [Kollar and Baird 1970].
FGF release activates the surrounding epithelium, which proliferates around the enamel knot and induces the transition from the bud to the cap stage [Thesleff et al.
Prior to laminar thickening, Pax9 expression is upregulated until the end of the cap stage, when it is reduced.
If Msx1 or Pax9 are not expressed, the mesenchyme will not be activated to release Bmp4, which in turn causes Lef1, Dlx2, Plx2, Ptc, and Fgf3, to not be expressed, and the tooth bud will not develop to the cap stage [Zhao et al.
Down-regulation of Msx1 causes a decrease in Fgf8; Fgf8 does not signal Fgf3; Fgf3 does not signal Syndecan-1; the absence of Syndecan-1 causes cessation of tooth development during the cap stage [Zhao et al.
During the cap stage, Wnt/[beta]-catenin is upregulated in the knot.
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