The non-canonical BMP and Wnt/β-catenin signaling pathways orchestrate early tooth development

Abstract

BMP and Wnt signaling pathways play a crucial role in organogenesis, including tooth development. Despite extensive studies, the exact functions, as well as if and how these two pathways act coordinately in regulating early tooth development, remain elusive. In this study, we dissected regulatory functions of BMP and Wnt pathways in early tooth development using a transgenic noggin (Nog) overexpression model (K14Cre;pNog). It exhibits early arrested tooth development, accompanied by reduced cell proliferation and loss of odontogenic fate marker Pitx2 expression in the dental epithelium. We demonstrated that overexpression of Nog disrupted BMP non-canonical activity, which led to a dramatic reduction of cell proliferation rate but did not affect Pitx2 expression. We further identified a novel function of Nog by inhibiting Wnt/β-catenin signaling, causing loss of Pitx2 expression. Co-immunoprecipitation and TOPflash assays revealed direct binding of Nog to Wnts to functionally prevent Wnt/β-catenin signaling. In situ PLA and immunohistochemistry on Nog mutants confirmed in vivo interaction between endogenous Nog and Wnts and modulation of Wnt signaling by Nog in tooth germs. Genetic rescue experiments presented evidence that both BMP and Wnt signaling pathways contribute to cell proliferation regulation in the dental epithelium, with Wnt signaling also controlling the odontogenic fate. Reactivation of both BMP and Wnt signaling pathways, but not of only one of them, rescued tooth developmental defects in K14Cre;pNog mice, in which Wnt signaling can be substituted by transgenic activation of Pitx2. Our results reveal the orchestration of non-canonical BMP and Wnt/β-catenin signaling pathways in the regulation of early tooth development.

Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration

“…Wnt signaling plays promotes early tooth development[29–31], whereas excessive Wnt attenuates late tooth development [32, 33]. Inactivation of TGFβ type I receptor (ALK5) in neural crest cells leads to delayed tooth initiation and development [34].…”

Fine tuning of Rac1 and RhoA alters cuspal shapes by remolding the cellular geometry

“…In general, tooth morphogenesis is a process that is regulated by epithelial-mesenchymal interactions and during which the oral ectoderm thickens, buds, and invaginates to form a cap-like structure, and then a species-specific cusp34. Based on a common morphogenetic concept that a specific shape arises from local differences in cellular behavior regulated by signaling molecules, the cusp formation process involves spatiotemporal changes in cell number, size, shape, and position56.…”

The interaction of secreted proteins Noggin4 and Wnt8 from Xenopus laevis embryos

“…Currently three subfamilies of the Noggin family are known: Noggin1, Noggin2, and Noggin4 [1][2][3][4][5]. The data obtained in our laboratory demonstrated that secreted regulators Noggin1 and Noggin2 were involved in the binding to the proper ligands and inhi bition of three essential signal cascades, BMP, Nodal/Activin, and Wnt/betaCatenin [6,7]. The functions of the Noggin4 protein, which shares 35% homology with other members of the Noggin family and was only found in inferior vertebrates, are still unknown.…”