The human EDAR 370V/A polymorphism affects tooth root morphology potentially through the modification of a reaction-diffusion system

Abstract

Morphological variations in human teeth have long been recognized and, in particular, the spatial and temporal distribution of two patterns of dental features in Asia, i.e., Sinodonty and Sundadonty, have contributed to our understanding of the human migration history. However, the molecular mechanisms underlying such dental variations have not yet been completely elucidated. Recent studies have clarified that a nonsynonymous variant in the ectodysplasin A receptor gene (EDAR 370V/A; rs3827760) contributes to crown traits related to Sinodonty. In this study, we examined the association between the EDAR polymorphism and tooth root traits by using computed tomography images and identified that the effects of the EDAR variant on the number and shape of roots differed depending on the tooth type. In addition, to better understand tooth root morphogenesis, a computational analysis for patterns of tooth roots was performed, assuming a reaction-diffusion system. The computational study suggested that the complicated effects of the EDAR polymorphism could be explained when it is considered that EDAR modifies the syntheses of multiple related molecules working in the reaction-diffusion dynamics. In this study, we shed light on the molecular mechanisms of tooth root morphogenesis, which are less understood in comparison to those of tooth crown morphogenesis.

Figure 1

Observation of tooth root morphology using CT. (A) Reconstruction of the three-dimensional surface and the occlusal plane (OP) using Amira ver 6.0.0. The number and shape of roots in the maxillary and mandibular teeth were observed in slice images parallel to the OP. (B–G) Examples of the tooth root morphology observed in UP1s (B), UP2s (C), UM1s (D), UM2s (E), LM1s (F), and LM2s (G). The arrows indicate the buccal (B) and mesial (M) directions.

Figure 2

Computational analysis of tooth root morphogenesis assuming a reaction–diffusion system. (A) Schema of the activator–inhibitor system. Interactions between two diffusible substances, namely activator and inhibitor, generate a self-organized spatial pattern. In this simulation, the EDAR variant is assumed to be associated with the self activation of activator and the activation of inhibitor by activator. (B–E) A representative result (left) and the summary (right) of 20 independent simulations. The variation in the cell pattern is caused depending on α_s (strength of activator synthesis) (B, C) and γ (strength of inhibitor synthesis) (D, E). In addition, “spotted” and “reverse-spotted” patterns are emerged under the conditions that the maximum concentration of the activator is high (u_max = 10 u₀; B, D) and low (u_max = 1.1 u₀; C, E), respectively. The blue color indicates a high concentration of the activator. Detailed conditions for computer simulations are described in “Materials and methods”, and parameter values used are as follows: α_s = 1.5–1.8 and γ = 1.0 (B, C); α_s = 1.8 and γ = 1.0–1.6 (D, E); α_m = 1.0 (B, D) or − 0.1 (C, E); and α_d = 1.0, β = 1.0, δ = 1.0, ε = 1.0, D_u = 0.25, D_v = 0.5, and u₀ = δε/[βγ − (α_s − α_d) δ] (B–E).

Figure 3

Schema of tooth root bifurcation. (A–D) Sagittal section and axial view of a developing human tooth at the stage of crown development (A) and at the stages of root development; before root bifurcation (B), during the dentin island formation (C), and after root bifurcation (D). The broken line denotes the sagittal section of the tooth. (E–H) Axial view of a developing tooth with one root (E), two roots (F), three roots (G), or a C-shaped root (H). The illustrations were created using Adobe Illustrator ver 24.