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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.

SUBMITTER: Jussila M

PROVIDER: S-EPMC6517835 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Jussila Maria M Aalto Anne J AJ Sanz Navarro Maria M Shirokova Vera V Balic Anamaria A Kallonen Aki A Ohyama Takahiro T Groves Andrew K AK Mikkola Marja L ML Thesleff Irma I

Development (Cambridge, England) 20151008 22

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 denta ...[more]

PMID: 26450968

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Project description:Dentinogenesis, a formation of dentin by odontoblasts, is an essential process during tooth development. Bone morphogenetic proteins (BMPs) are one of the most crucial growth factors that contribute to dentin formation. However, it is still unclear how BMP signaling pathways regulate postnatal crown and root dentinogenesis. BMPs transduce signals through canonical Smad and non-Smad signaling pathways including p38 and ERK signaling pathways. To investigate the roles of Smad and non-Smad signaling pathways in dentinogenesis, we conditionally deleted Bmpr1a, which encodes the type 1A receptor for BMPs, to remove both Smad and non-Smad pathways in Osterix-expressing cells. We also expressed a constitutively activated form of Bmpr1a (caBmpr1a) to increase Smad1/5/9 signaling activity without altered non-Smad activity in odontoblasts. To understand the function of BMP signaling during postnatal dentin formation, Cre activity was induced at the day of birth. Our results showed that loss of BmpR1A in odontoblasts resulted in impaired dentin formation and short molar roots at postnatal day 21. Bmpr1a cKO mice displayed a reduction of dentin matrix production compared to controls associated with increased cell proliferation and reduced Osx and Dspp expression. In contrast, caBmpr1a mutant mice that show increased Smad1/5/9 signaling activity resulted in no overt tooth phenotype. To further dissect the functions of each signaling activity, we generated Bmpr1a cKO mice also expressing caBmpr1a to restore only Smad1/5/9 signaling activity. Restoring Smad activity in the compound mutant mice rescued impaired crown dentin formation in the Bmpr1a cKO mice; however, impaired root dentin formation and short roots were not changed. These results suggest that BMP-Smad signaling in odontoblasts is responsible for crown dentin formation, while non-Smad signaling may play a major role in root dentin formation and elongation. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Project description:Although genes on the human X chromosome reportedly influence tooth crown morphology, little is known about X chromosome activation or inactivation systems relevant to morphological variations. We assessed the relationships between tooth crown size and crown morphological traits in females with Turner syndrome, the variants of which include complete absence of one X chromosome, lack of the short arm (Xp), or duplication of the long arms (Xq), and then estimated the functions of Xp and Xq in the process of unilateral X chromosome inactivation during tooth crown development. The mesiodistal and buccolingual diameters in the maxillary first (M1) and second (M2) permanent molars were compared among X chromosome karyotypes by multiple regression analyses, and their relationships with the development of Carabelli's cusp and the distolingual cusp were analyzed using logistic regression analysis. The crown sizes increased in the order of the 46,X,i(Xq) karyotype, 45,X and 45,X/46,XX karyotypes, and control group. A lower frequency of Carabelli's cusp and higher frequency of a reduced distolingual cusp in M1 were characteristics of Turner syndrome. The overall M1 and M2 crown sizes differed among the X chromosome karyotypes, whereas a smaller crown size was associated with a reduced distolingual cusp but not with Carabelli's cusp. Considering the differences in chromosome arrangement among females with Turner syndrome and the process of unilateral X chromosome inactivation, the observed results can be considered in terms of quantity or number of promoters/inhibitors during tooth crown development. The X chromosome karyotypes have a strong influence on the overall crown sizes of the M1 and M2 molars because those karyotypes with variable numbers of active gene regions directly influence tooth germ development in an early stage of human odontogenesis. The later forming cusps, such as the distolingual cusp and Carabelli's cusp, may be affected by this developmental prerequisite.

Dataset Information

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

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

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