The Impact of the Eda Pathway on Tooth Root Development

Abstract

The Eda pathway ( Eda, Edar, Edaradd) plays an important role in tooth development, determining tooth number, crown shape, and enamel formation. Here we show that the Eda pathway also plays a key role in root development. Edar (the receptor) is expressed in Hertwig's epithelial root sheath (HERS) during root development, with mutant mice showing a high incidence of taurodontism: large pulp chambers lacking or showing delayed bifurcation or trifurcation of the roots. The mouse upper second molars in the Eda pathway mutants show the highest incidence of taurodontism, this enhanced susceptibility being matched in human patients with mutations in EDA-A1. These taurodont teeth form due to defects in the direction of extension of the HERS from the crown, associated with a more extensive area of proliferation of the neighboring root mesenchyme. In those teeth where the angle at which the HERS extends from the crown is very wide and therefore more vertical, the mutant HERSs fail to reach toward the center of the tooth in the normal furcation region, and taurodont teeth are created. The phenotype is variable, however, with milder changes in angle and proliferation leading to normal or delayed furcation. This is the first analysis of the role of Eda in the root, showing a direct role for this pathway during postnatal mouse development, and it suggests that changes in proliferation and angle of HERS may underlie taurodontism in a range of syndromes.

Antagonistic interaction between Ezh2 and Arid1a coordinates root patterning and development via Cdkn2a in mouse molars

“…For instance, the Eda pathway is specifically active in HERS in mouse molars. Cell proliferation activity is altered in the dental mesenchyme in Eda mutant molars with delayed furcation formation, suggesting that epithelial-derived signals may regulate furcation development through epithelial-mesenchymal interaction (Fons Romero et al, 2017). Recent studies have begun to explore the role of the dental mesenchyme in regulating root patterning and furcation development.…”

“…However, the mechanisms involved in HERS regulation of furcation development remain unknown. Although previous studies have shown that changes in cell proliferation activity in the dental mesenchyme can lead to furcation defects (Fons Romero et al, 2017; Sohn et al, 2014), it is not clear whether the instructions that ultimately determine root furcation development and number reside in the dental mesenchyme or epithelium.…”

Missense Pathogenic variants in KIF4A Affect Dental Morphogenesis Resulting in X-linked Taurodontism, Microdontia and Dens-Invaginatus

“…Late timing or failure of Hertwig’s epithelial root sheath (HERS) invagination may be responsible for the apical shift of the root furcation in taurodontism (Yang et al, 2015). Pathogenic variants in genes in the Eda receptor ligand pair, particularly Eda and Edar, may result in taurodontism of some molar teeth as a result of changes in the proliferation and angle of HERS (Fons Romero et al, 2017).…”

An Essential Requirement for Fgf10 in Pinna Extension Sheds Light on Auricle Defects in LADD Syndrome

“…For BrdU, 2M HCl at 37 o C was used before addition of the primary antibody. In situ hybridization was performed as previously described ( Fons Romero et al, 2017 ). Immunolabelings and in situ hybridization reactions were repeated at least 3 times to confirm the expression patterns.…”