Suppression of epithelial differentiation by Foxi3 is essential for molar crown patterning

Abstract

Epithelial morphogenesis generates the shape of the tooth crown. This is driven by patterned differentiation of cells into enamel knots, root-forming cervical loops and enamel-forming ameloblasts. Enamel knots are signaling centers that define the positions of cusp tips in a tooth by instructing the adjacent epithelium to fold and proliferate. Here, we show that the forkhead-box transcription factor Foxi3 inhibits formation of enamel knots and cervical loops and thus the differentiation of dental epithelium in mice. Conditional deletion of Foxi3 (Foxi3 cKO) led to fusion of molars with abnormally patterned shallow cusps. Foxi3 was expressed in the epithelium, and its expression was reduced in the enamel knots and cervical loops and in ameloblasts. Bmp4, a known inducer of enamel knots and dental epithelial differentiation, downregulated Foxi3 in wild-type teeth. Using genome-wide gene expression profiling, we showed that in Foxi3 cKO there was an early upregulation of differentiation markers, such as p21, Fgf15 and Sfrp5. Different signaling pathway components that are normally restricted to the enamel knots were expanded in the epithelium, and Sostdc1, a marker of the intercuspal epithelium, was missing. These findings indicated that the activator-inhibitor balance regulating cusp patterning was disrupted in Foxi3 cKO. In addition, early molar bud morphogenesis and, in particular, formation of the suprabasal epithelial cell layer were impaired. We identified keratin 10 as a marker of suprabasal epithelial cells in teeth. Our results suggest that Foxi3 maintains dental epithelial cells in an undifferentiated state and thereby regulates multiple stages of tooth morphogenesis.

Epithelial Markers aSMA, Krt14, and Krt19 Unveil Elements of Murine Lacrimal Gland Morphogenesis and Maturation

“…As a result, it was impossible to use it for any genetic fate mapping experiment. Therefore, we took advantage of the K14-Cre43 mouse strain, reported to have a high recombination efficiency in various ectodermal organs (Jussila et al, 2015 ; Shirokova et al, 2016 ). It allowed the visualization of the LG epithelial morphological changes from E15 to E18 (Figure 4A ).…”

A comparison of transcriptomic patterns measured in the skin of Chinese fine and coarse wool sheep breeds

“…Further, the mutation of FOXI3 can cause the hairless phenotype in dogs 51 – 53 . Specific expression of the FOXI3 protein in the epithelium of the hair, whisker placodes and developing teeth has been shown to provide essential signals for the development 54 , 55 . In respect of morphogenesis and cycling of the hair follicle, expression of FOXI3 can be thought of as a secondary marker for the hair germ structure 56 .…”

TGF-β Family Signaling in Epithelial Differentiation and Epithelial–Mesenchymal Transition

“…Accordingly, inactivation of Msx2 and Foxn1 in the germline causes extensive proliferation of primitive mes-enchymal cells that cannot progress to terminal differentiation, and thus nail development is severely defective (Cai and Ma 2011). The common processes that shape differentiation into hairs and nails are also highlighted by studies of the transcription factor FoxI3, whose expression is induced by activin A in epithelial cells (Shirokova et al 2013), and is required for hair, tooth, and nail development (Jussila et al 2015;Shirokova et al 2016).…”