Interplay between EDA-EDAR and WNT signalling pathways in the development of skin appendages in hypohidrotic ectodermal dysplasia

Ectodermal dysplasia comprises a group of hereditary disorders affecting the development of the skin and its appendages. Among the more than 150 characterised forms of ectodermal dysplasia, hypohidrotic ectodermal dysplasia is the most prevalent in children. Hypohidrotic ectodermal dysplasia is marked by reduced sweating, sparse hair, a limited number of conical-shaped teeth, and brittle nails. The condition results from mutations in genes involved in the EDA-EDAR-EDARADD-NF-κB signalling pathway, which is crucial for early epithelial-mesenchymal communication during the formation of skin appendages. The Wnt/β-catenin pathway also plays a vital role in the development of hair follicles, teeth, and other ectodermal structures. In this article, publicly available single-cell gene expression data from a mouse model were re-analysed to investigate the expression profiles of genes from both the EDA-EDAR and WNT pathways. Wnt10b, Dkk4 and Edar were confirmed to be expressed in epidermal keratinocytes, particularly in Fgf20-positive early placode-forming cells. Furthermore, correlated expression of Edaradd and NF-κB was observed during early appendage formation, while Eda ligand expression was detected in Dkk1-positive mesenchymal progenitor cells, transiently amplifying to become the first dermal condensate and subsequently dermal papilla cells. These findings further support previous observations that EDA-A1 signalling through EDAR-EDARADD and NF-κB enhances WNT pathway activity, creating a mutually reinforcing network. Disruption of this feedback loop between the EDA-EDAR and WNT pathways give rise to the characteristic phenotypes of hypohidrotic ectodermal dysplasia observed in children. Early restoration of the EDA-EDAR and WNT signalling pathways may offer a promising therapeutic strategy for rescuing skin appendage development and thus reducing the effects of ectodermal dysplasias in the future.