AUTHOR=Aurrekoetxea Maitane , Irastorza Igor , García-Gallastegui Patricia , Jiménez-Rojo Lucia , Nakamura Takashi , Yamada Yoshihiko , Ibarretxe Gaskon , Unda Fernando J. 

TITLE=Wnt/β-Catenin Regulates the Activity of Epiprofin/Sp6, SHH, FGF, and BMP to Coordinate the Stages of Odontogenesis

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=4

YEAR=2016

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2016.00025

DOI=10.3389/fcell.2016.00025

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> We used an <italic>in vitro</italic> tooth development model to investigate the effects of overactivation of the Wnt/β-catenin pathway during odontogenesis by bromoindirubin oxime reagent (BIO), a specific inhibitor of GSK-3 activity.</p><p><bold>Results:</bold> Overactivating the Wnt/β-catenin pathway at tooth initiation upregulated and ectopically expressed the epithelial markers <italic>Sonic Hedgehog (Shh), Epiprofin (Epfn), and Fibroblast growth factor8 (Fgf8)</italic>, which are involved in the delimitation of odontogenic fields in the oral ectoderm. This result indicated an ectopic extension of the odontogenic potential. During tooth morphogenesis, <italic>Fibroblast growth factor4 (Fgf4), Fibroblast growth factor10 (Fgf10), Muscle segment homeobox 1 (Msx-1), Bone Morphogenetic protein 4 (Bmp4), and Dickkopf WNT signaling pathway inhibitor 1 (Dkk-1)</italic> were overexpressed in first molars cultured with BIO. Conversely, the expression levels of <italic>Wingless integration site 10b (Wnt-10b)</italic> and <italic>Shh</italic> were reduced. Additionally, the odontoblast differentiation markers Nestin and <italic>Epfn</italic> showed ectopic overexpression in the dental mesenchyme of BIO-treated molars. Moreover, alkaline phosphatase activity increased in the dental mesenchyme, again suggesting aberrant, ectopic mesenchymal cell differentiation. Finally, Bmp4 downregulated <italic>Epfn</italic> expression during dental morphogenesis.</p><p><bold>Conclusions:</bold> We suggest the presence of a positive feedback loop wherein <italic>Epfn</italic> and β<italic>-catenin</italic> activate each other. The balance of the expression of these two molecules is essential for proper tooth development. We propose a possible link between Wnt, Bmp, and Epfn that would critically determine the correct patterning of dental cusps and the differentiation of odontoblasts and ameloblasts.</p>