Reciprocal Requirements for EDA/EDAR/NF-κB and Wnt/β-Catenin Signaling Pathways in Hair Follicle Induction

Abstract

SUMMARY Wnt/β-catenin and NF-κB signaling mechanisms provide central controls in development and disease, but how these pathways intersect is unclear. Using hair follicle induction as a model system, we show that patterning of dermal Wnt/β-catenin signaling requires epithelial β-catenin activity. We find that Wnt/β-catenin signaling is absolutely required for NF-κB activation, and that Edar is a direct Wnt target gene. Wnt/β-catenin signaling is initially activated independently of Eda/Edar/NF-κB activity in primary hair follicle primordia. However, Eda/Edar/NF-κB signaling is required to refine the pattern of Wnt/β-catenin activity, and to maintain this activity at later stages of placode development. We show that maintenance of localized expression of Wnt10b and Wnt10a requires NF-κB signaling, providing a molecular explanation for the latter observation, and identify Wnt10b as a direct NF-κB target. These data reveal a complex interplay and inter-dependence of Wnt/β-catenin and Eda/Edar/NF-κB signaling pathways in initiation and maintenance of primary hair follicle placodes.

Variability in dentofacial phenotypes in four families with WNT10A mutations

“…WNT genes are involved in hair-follicle morphogenesis, 27,28 skin and tooth embryogenesis [29][30][31] and several other developmental processes. 32 It also explains that in addition to TA, hypoplastic morphological dental features, including conical tooth shapes and microdontia, occur in the permanent teeth which did develop.…”

Development and Homeostasis of the Skin Epidermis

“…Their simultaneous deletion leads to rapid HF disappearance (Nguyen et al 2009). b-Catenin signaling acts upstream of the Eda-A1/Edar/NF-kB signaling pathway, which controls HF morphogenesis during the early stage of HF specification, but EDA/EDAR/NF-kB activity helps to sustain Wnt activity at latter stages (Zhang et al 2009a). Although overexpression of b-catenin during adult homeostasis leads to de novo HF formation from the IFE and SG and to a lesser extent from HF, high levels of b-catenin signaling during embryonic development lead to expansion of HF placodes, which fail to down-grow and differentiate.…”

Generation and Characterization of Function-blocking Anti-ectodysplasin A (EDA) Monoclonal Antibodies That Induce Ectodermal Dysplasia

“…appendage formation are first marked by activation of the Wnt/ ␤-catenin signaling pathway in the embryonic skin epithelium (1)(2)(3). The action of the TNF family ligand EDA 2 on its receptor EDAR, a target gene of Wnt signaling, is required shortly thereafter at least for sweat glands and some hair types, to stimulate the transcription factor NF-B, itself necessary for the formation of morphologically distinct cellular condensates called placodes (3,4).…”