Ring1a/b polycomb proteins regulate the mesenchymal stem cell niche in continuously growing incisors

Abstract

Rodent incisors are capable of growing continuously and the renewal of dental epithelium giving rise to enamel-forming ameloblasts and dental mesenchyme giving rise to dentin-forming odontoblasts and pulp cells is achieved by stem cells residing at their proximal ends. Although the dental epithelial stem cell niche (cervical loop) is well characterized, little is known about the dental mesenchymal stem cell niche. Ring1a/b are the core Polycomb repressive complex1 (PRC1) components that have recently also been found in a protein complex with BcoR (Bcl-6 interacting corepressor) and Fbxl10. During mouse incisor development, we found that genes encoding members of the PRC1 complex are strongly expressed in the incisor apical mesenchyme in an area that contains the cells with the highest proliferation rate in the tooth pulp, consistent with a location for transit amplifying cells. Analysis of Ring1a(-/-);Ring1b(cko/cko) mice showed that loss of Ring1a/b postnatally results in defective cervical loops and disturbances of enamel and dentin formation in continuously growing incisors. To further characterize the defect found in Ring1a(-/-);Ring1b(cko/cko) mice, we demonstrated that cell proliferation is dramatically reduced in the apical mesenchyme and cervical loop epithelium of Ring1a(-/-);Ring1b(cko/cko) incisors in comparison to Ring1a(-/-);Ring1b(fl/fl)cre- incisors. Fgf signaling and downstream targets that have been previously shown to be important in the maintenance of the dental epithelial stem cell compartment in the cervical loop are downregulated in Ring1a(-/-);Ring1b(cko/cko) incisors. In addition, expression of other genes of the PRC1 complex is also altered. We also identified an essential postnatal requirement for Ring1 proteins in molar root formation. These results show that the PRC1 complex regulates the transit amplifying cell compartment of the dental mesenchymal stem cell niche and cell differentiation in developing mouse incisors and is required for molar root formation.

Cellular and molecular mechanisms of tooth root development

“…Specifically, deletion of Bmp2 in osterixpositive mesenchymal progenitor cells causes abnormal odontoblast differentiation and short roots (Rakian et al, 2013). Moreover, restriction of Bmp4 expression in the dental mesenchyme by Ring proteins, which contain a characteristic zinc-finger domain that mediates protein-protein interactions, affects odontoblast differentiation and root formation (Lapthanasupkul et al, 2012). To date, however, the precise regulatory function of mesenchymal Bmp signaling during root development remains unclear.…”

From Flies to Mice: The Emerging Role of Non-Canonical PRC1 Members in Mammalian Development

“…Others also found that failure in S-phase entry, proliferative arrest and p21 upregulation in Ring1/Rnf2 double mutant cells [236]. In vivo studies found that Bmp signaling is altered in the mandibular molar of Ring1 −/− ; Rnf2 cko/cko mice [237].…”

Dental mesenchymal stem cells

“…This rapidly dividing population in the incisor represents the cells that differentiate, and thus the transition from a slow-cycling stem cell to a rapidly cycling progenitor is a critically important yet poorly understood process. The transit-amplifying cells are the most rapidly cycling cells in the incisor pulp and they are located immediately distal to the slowcycling stem cells (Lapthanasupkul et al, 2012). These cells express specific genes, most notably those of the polycomb repressive complex 1 (Prc1), that are generally not expressed in the surrounding cells and which are important for cell proliferation (Lapthanasupkul et al, 2012).…”

“…The transit-amplifying cells are the most rapidly cycling cells in the incisor pulp and they are located immediately distal to the slowcycling stem cells (Lapthanasupkul et al, 2012). These cells express specific genes, most notably those of the polycomb repressive complex 1 (Prc1), that are generally not expressed in the surrounding cells and which are important for cell proliferation (Lapthanasupkul et al, 2012). Targeted deletion of genes integral to Prc1, such as Ring1a (Ring1) and Ring1b (Rnf2), results in the arrest of incisor growth and loss of transit-amplifying cells, suggesting that a functional Prc1 complex is essential to maintain proliferation in these cells.…”