TNF Signaling via the Ligand–Receptor Pair Ectodysplasin and Edar Controls the Function of Epithelial Signaling Centers and Is Regulated by Wnt and Activin during Tooth Organogenesis

Abstract

Ectodermal dysplasia syndromes affect the development of several organs, including hair, teeth, and glands. The recent cloning of two genes responsible for these syndromes has led to the identification of a novel TNF family ligand, ectodysplasin, and TNF receptor, edar. This has indicated a developmental regulatory role for TNFs for the first time. Our in situ hybridization analysis of the expression of ectodysplasin (encoded by the Tabby gene) and edar (encoded by the downless gene) during mouse tooth morphogenesis showed that they are expressed in complementary patterns exclusively in ectodermal tissue layer. Edar was expressed reiteratively in signaling centers regulating key steps in morphogenesis. The analysis of the effects of eight signaling molecules in the TGFbeta, FGF, Hh, Wnt, and EGF families in tooth explant cultures revealed that the expression of edar was induced by activinbetaA, whereas Wnt6 induced ectodysplasin expression. Moreover, ectodysplasin expression was downregulated in branchial arch epithelium and in tooth germs of Lef1 mutant mice, suggesting that signaling by ectodysplasin is regulated by LEF-1-mediated Wnt signals. The analysis of the signaling centers in tooth germs of Tabby mice (ectodysplasin null mutants) indicated that in the absence of ectodysplasin the signaling centers were small. However, no downstream targets of ectodysplasin signaling were identified among several genes expressed in the signaling centers. We conclude that ectodysplasin functions as a planar signal between ectodermal compartments and regulates the function, but not the induction, of epithelial signaling centers. This TNF signaling is tightly associated with epithelial-mesenchymal interactions and with other signaling pathways regulating organogenesis. We suggest that activin signaling from mesenchyme induces the expression of the TNF receptor edar in the epithelial signaling centers, thus making them responsive to Wnt-induced ectodysplasin from the nearby ectoderm. This is the first demonstration of integration of the Wnt, activin, and TNF signaling pathways.

Traf6 is essential for murine tooth cusp morphogenesis

“…The position of Troy-expressing cells in the enamel knot was indistinguishable from expression of Edar and Edaradd, but Troy was expressed at higher levels ( Fig. 1E,F ;Tucker et al, 2000;Headon et al, 2001;Laurikkala et al, 2001). Currently, the expression pattern of Xedar in tooth development is not known.…”

“…Expression of Edar and Edaradd during tooth development have been described and linked to the primary enamel knots (Tucker et al, 2000;Headon et al, 2001;Laurikkala et al, 2001). Abnormal enamel knots have been found in Eda and Edar mutant mice (Pispa et al, 1999;Tucker et al, 2000;Laurikkala et al, 2001), although the defects in enamel knots are distinct with smaller enamel knots occurring in Eda mutant mice, whereas Edar mutant mice have extended lope-like enamel knots. Abnormal cusp formation have been found in Edaradd mutant mice, but the enamel knot phenotype has not been reported (Sofaer, 1969a(Sofaer, ,b, 1977(Sofaer, , 1979.…”

“…tabby mice carry a mutation in the tumor necrosis factor (TNF) family ligand Ectodysplasin (Eda), downless are mutated in the receptor for Eda (Edar), and crinkled have mutations in an Edar adaptor protein Edaradd (Kere et al, 1996;Headon and Overbeek, 1999;Headon et al, 2001). In tabby, downless, and crinkled mice, molar tooth cusps are rounded and reduced in height (Sofaer, 1969a(Sofaer, ,b, 1977(Sofaer, , 1979Pispa et al, 1999;Tucker et al, 2000;Laurikkala et al, 2001).…”

Intercellular growth factor signaling and the development of mouse tracheal submucosal glands

“…In vitro experiments have suggested that Eda is directly regulated by Wnt signaling in the tooth bud (Pengue et al, 1999;Laurikkala et al, 2001;Durmowicz et al, 2002).…”

Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits

“…19,20 Animal models have also suggested that the EDA/EDAR pathway regulates the development of ectodermal derivative. [21][22][23][24][25][26][27][28][29] It is also worth noting that, in studies on human population genetics, a strong signal of positive selection in Asian populations has been observed for the EDAR 370A allele. Specifically, the allele is rare in African and European populations and is associated with a long-ranged uniform haplotype in Asian populations.…”