WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation

Abstract

Human WNT10A mutations are associated with developmental tooth abnormalities and adolescent onset of a broad range of ectodermal defects. Here we show that β-catenin pathway activity and adult epithelial progenitor proliferation are reduced in the absence of WNT10A, and identify Wnt-active self-renewing stem cells in affected tissues including hair follicles, sebaceous glands, taste buds, nails and sweat ducts. Human and mouse WNT10A mutant palmoplantar and tongue epithelia also display specific differentiation defects that are mimicked by loss of the transcription factor KLF4. We find that β-catenin interacts directly with region-specific LEF/TCF factors, and with KLF4 in differentiating, but not proliferating, cells to promote expression of specialized keratins required for normal tissue structure and integrity. Our data identify WNT10A as a critical ligand controlling adult epithelial proliferation and region-specific differentiation, and suggest downstream β-catenin pathway activation as a potential approach to ameliorate regenerative defects in WNT10A patients.

Role of WNT10A in failure of tooth development in humans and zebrafish

“…; Xu et al. ). Here, we report the clinical and functional impact of a compound heterozygous mutation in WNT10A (c.637G>A (p.Gly213Ser); c.1070C>T (p.Thr357Ile) as likely pathogenic for isolated oligodontia, and demonstrate that perturbations in wnt10a expression impairs normal tooth development in zebrafish embryos.…”

“…; Xu et al. ). These findings are opposite to the phenotypes consistently reported for individuals with WNT10A variants in all reported human genetic studies.…”

“…Numerous studies have implicated a major role for WNT10A in the etiology of tooth agenesis in humans (van den Boogaard et al 2012), despite the opposing supernumerary teeth phenotype observed in Wnt10a null mice (Yang et al 2015;Xu et al 2017). Here, we report the clinical and functional impact of a compound heterozygous mutation in WNT10A (c.637G>A (p.Gly213-Ser); c.1070C>T (p.Thr357Ile) as likely pathogenic for isolated oligodontia, and demonstrate that perturbations in wnt10a expression impairs normal tooth development in zebrafish embryos.…”

“…Expression of Wnt10a induced and colocalized with mRNA expression of Dspp (a key molecule for dentin mineralization) in fully differentiated secretory odontoblasts, indicating that Wnt10a is potentially involved in dentin mineralization events as an upstream regulator of Dspp (Yamashiro et al 2007). Interestingly, however, Wnt10a-null and -mutant mice show supernumerary teeth (instead of missing teeth) and molar teeth characterized by taurodontism and altered molar crown morphology (Yang et al 2015;Xu et al 2017). These findings are opposite to the phenotypes consistently reported for individuals with WNT10A variants in all reported human genetic studies.…”

Single cell transcriptomics of human epidermis reveals basal stem cell transition states

“…WNT signaling is a pleotropic signaling pathway heavily involved from the earliest stages of skin development where it helps specify the ectoderm down the skin epithelium lineage (Wilson et al, 2001) and helps specify skin appendages (Kratochwil et al, 1996). WNT signaling is also involved in adult skin homeostasis where overexpression or loss of WNT/beta-catenin results in a variety of intra-and interfollicular epidermis phenotypes (Andl et al, 2002;Choi et al, 2013;Xu et al, 2017;Zhang et al, 2009).…”