Signaling Pathways Critical for Tooth Root Formation

Abstract

Tooth is made of an enamel-covered crown and a cementum-covered root. Studies on crown dentin formation have been a major focus in tooth development for several decades. Interestingly, the population prevalence for genetic short root anomaly (SRA) with no apparent defects in crown is close to 1.3%. Furthermore, people with SRA itself are predisposed to root resorption during orthodontic treatment. The discovery of the unique role of Nfic (nuclear factor I C; a transcriptional factor) in controlling root but not crown dentin formation points to a new concept: tooth crown and root have different control mechanisms. Further genetic mechanism studies have identified more key molecules (including Osterix, β-catenin, and sonic hedgehog) that play a critical role in root formation. Extensive studies have also revealed the critical role of Hertwig's epithelial root sheath in tooth root formation. In addition, Wnt10a has recently been found to be linked to multirooted tooth furcation formation. These exciting findings not only fill the critical gaps in our understanding about tooth root formation but will aid future research regarding the identifying factors controlling tooth root size and the generation of a whole "bio-tooth" for therapeutic purposes. This review starts with human SRA and mainly focuses on recent progress on the roles of NFIC-dependent and NFIC-independent signaling pathways in tooth root formation. Finally, this review includes a list of the various Cre transgenic mouse lines used to achieve tooth root formation-related gene deletion or overexpression, as well as strengths and limitations of each line.

Keywords: NFIC; cell signaling; dentin; odontogenesis; osterix; tooth regeneration.

Figure 1.

Diagram showing root morphogenesis in 2 stages: root initiation and root elongation. HERS is formed by fusion of outer enamel epithelium (OEE) and inner enamel epithelium (IEE), which marks the initiation of root formation. The odontoblasts derived from the dental papilla (apical papilla at root elongation stage) form dentin, whereas there are 2 stem cell niches giving rise to cementoblasts (Cb), including the dental follicle (dashed red arrow) and HERS (dashed blue arrow). Some HERS cells eventually become epithelial rests of Malassez (ERM). DFC, dental follicle cell; HERS, Hertwig’s epithelial root sheath; SI, stratum intermedium; SR, stellate reticulum.

Figure 2.

Osterix, 1 of the key downstream molecules of NFIC, plays a crucial role in root but not crown formation. (a) The 2-wk-old Nfic-KO displayed short molar roots as viewed by micro–computed tomography (right panel). (b) Immunohistochemistry stains showed few positive Osx signals in the Nfic-KO odontoblasts (right panel). Red arrow indicates few positive OSX signals in the KO odontoblasts. (c) The 2-wk-old Osx-cKO molar roots (right) were short and thin according to micro–computed tomography images. (d) The Osx-cKO showed short incisor root analogue according to x-ray images. Red arrows indicate the Osx-cKO short incisor root-analogue. (e) The hematoxylin and eosin stain documented an immature odontoblast cell layer with no sign of polarization morphology in the Osx-cKO root (right panel). (f) The in situ hybridization assays displayed a great decrease in Dspp in the Osx-cKO root (right panel). (g) Osx is the key downstream molecule of NFIC, which controls root but not crown formation via its inhibitory role in cell proliferation and stimulatory function in the cell differentiation/odontoblast process formation, partially through DSPP (right panel). DSPP, dentin sialophosphoprotein; KO, knockout; Od, odontoblast; OSX, Osterix; WT, wild type. Panels A to G adapted and reproduced with permission from Zhang et al., J Bone Mineral Res, , copyright John Wiley & Sons.

Figure 3.

Diagram showing the Cre transgenic mouse lines applied in tooth root formation studies. HERS, Hertwig’s epithelial root sheath; Od, odontoblast.

Figure 4.

Diagram showing the current major molecular pathways regulating root formation via an interaction between Hertwig’s epithelial root sheath (HERS) and dental mesenchymal cells. BMP, bone morphogenetic protein; TGF-β, transforming growth factor β.