Mesenchymal TGF-βSignaling Orchestrates Dental Epithelial Stem Cell Homeostasis Through Wnt Signaling

Abstract

In mouse, continuous growth of the postnatal incisor is coordinated by two populations of multipotent progenitor cells, the dental papilla mesenchymal cells and dental epithelial stem cells, residing at the proximal end of the incisor, yet the molecular mechanism underlying the cooperation between mesenchymal and epithelial cells is largely unknown. Here, transforming growth factor-b (TGF-b) type II receptor (Tgfbr2) was specifically deleted within the postnatal dental papilla mesenchyme. The Tgfbr2-deficient mice displayed malformed incisors with wavy mineralized structures at the labial side as a result of increased differentiation of dental epithelial stem cells. We found that mesenchymal Tgfbr2 disruption led to upregulated expression of Wnt5a and downregulated expression of Fgf3/10 in the mesenchyme, both of which synergistically enhanced Lrp5/6-b-catenin signaling in the cervical loop epithelium. In accord with these findings, mesenchyme-specific depletion of the Wnt transporter gene Wls abolished the aberrant mineralized structures caused by Tgfbr2 deletion. Thus, mesenchymal TGF-b signaling provides a unifying mechanism for the homeostasis of dental epithelial stem cells via a Wnt signalingmediated mesenchymal-epithelial cell interaction.

TGF-β Family Signaling in Embryonic and Somatic Stem-Cell Renewal and Differentiation

“…Conditional deletion of Tgfb2 in the dental mesenchyme is associated with increased DESC differentiation, malformation of the incisors, decreased expression of FGF3 and FGF10, and increased expression of Wnt5. The effects of Tgfb2 deletion could be partially rescued by inhibition of Wnt signaling, suggesting that mesenchymal TGF-β2 production controls Wnt and FGF10 expression to regulate DESC maintenance and differentiation (Yang et al, 2014). The phenotype observed with loss of Smad4 expression is likely due to loss of BMP signaling, as dental mesenchyme produces BMP-4, which inhibits FGF3 expression (Wang et al, 2007) and suggests that Smad4 may play a larger role in mediating BMP signaling in this niche compared to TGF-β signaling.…”

Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells

“…Fortunately, new tools are available to better address the tissuespecific functions of Wnts. [19][20][21][22][23][24] All Wnts are posttranslationally modified in the endoplasmic reticulum by addition of a palmitoleate moiety that is required both for their secretion and for binding to their cell-surface receptor Frizzled. [25][26][27][28] Wnt palmitoleation is catalyzed by PORCN, a nonredundant membrane-bound O-acyl transferase.…”

Does murine spermatogenesis require WNT signalling? A lesson from Gpr177 conditional knockout mouse models

“…Sebsequently, these Gpr177 cKO mouse lines have been utilised to investigate the roles of WNT signalling and WNTs in a variety of tissues, such as embryonic hair follicles, fungiform placodes and teeth. 39, 40, 41, 42 …”