EDA signaling and skin appendage development

Abstract

The same morphogenetic signals are often involved in the development of different organs. For developing skin appendages, a model for tissue-specific regulation of signaling is provided by the EDA pathway, which accesses the otherwise ubiquitous NFkappaB transcription factors. EDA signaling is mediated by ectodysplasin, EDAR and EDARADD, which form a new TNF ligand-receptor-adaptor family that is restricted to skin appendages in vertebrates from fish to human. The critical function of the pathway was demonstrated in the hereditary genetic disorder Anhidrotic Ectodermal Dysplasia (EDA), which is characterized by defective formation of hair follicles, sweat glands and teeth. The pathway does not appear to initiate the development of the appendages, but is regulated by and regulates the course of further morphogenesis. In mice, transgenic and knockout strains have increasingly revealed features of the mechanism, and suggest possible non-invasive interventions to alleviate EDA deficiency, especially in sweat glands and eyes.

Figure 1

Schematic representation of EDA signaling. EDA is expressed in interfollicular cells; its receptor EDAR in follicular cells. Wnt/Lef1 and other putative signals (GATA, Nkx2 and ???) regulate transcription. The protein product ectodysplasin, is cleaved by furine-like proteases and bind to its receptor EDAR to initiate EDA signaling. EDAR recruits the cytoplasmic signaling adaptor protein EDRADD, and via TRAF6/TAK1/TAB2, the signaling activates the NEMO/IKK complex. That complex phosphorylates IkBs, leading to the entry of NFκBs into the nucleus and the activation of cognate gene transcription. Reported targets of EDA signaling include Wnt/Dkks, Shh, BMP/Sostdc1, LTβ and madcam1. EDA signaling may feedback regulate the Wnt pathway through Dkk4 and Dkk1. Asterisks indicate mutants that cause EDA-like phenotypes in patients and/or mouse models. Mutations in TRAF6, NEMO, IkBα or NFκBs also produce EDA-like phenotypes, but accompanied by immunodeficiency.

Figure 2

Conservation of the EDAR protein during evolution. Complete (red) or partial (blue) homology of EDAR sequence tracts conserved between species. TNFR, transmembrane, and cytoplasmic death-domains (DD) are shown in thin, thick, and dotted underlines, respectively. H, human, M, mouse, C, chicken, X, xenopus, F, medaka fish.