The fundamentals of WNT10A

Abstract

Human wingless-type MMTV integration site family member 10A (WNT10A) is a secreted glycoprotein that is involved in signaling pathways essential to ectodermal organogenesis and tissue regeneration. WNT10A was first linked to human disorders in 2006, demonstrating a WNT10a variant to be associated with cleft lip with/without cleft palate. Numerous publications have since then identified the importance of WNT10A in the development of ectodermal appendages and beyond. In this review, we provide information on the structure of the WNT10A gene and protein, summarize its expression patterns in different animal models and in human, and describe the identified roles in tissue and organ development and repair in the different animal model organisms. We then correlate such identified functions and working mechanisms to the pathophysiology of a spectrum of human diseases and disorders that result from germline loss-of-function mutations in WNT10A, including ectodermal dysplasia (ED) syndromes Odonto-oncho-dermal dysplasia (OODD), Schöpf-Schulz-Passarge syndrome (SSPS), and selective tooth agenesis, as well as pathological conditions like fibrosis and carcinogenesis that can be correlated with increased WNT10A activity (Section 5).

Keywords: Mouse; Odonto-oncho-dermal dysplasia; Schöpf–schulz–passarge syndrome; Tooth agenesis; Zebrafish; wnt10a.

Fig. 1.

Genomic and domain structure of human WNT10A. A. Genomic organization of human WNT10A. Base location are derived from Genome Reference Consortium Human Build 38 (GRCh38.p14). B. Exon structure of WNT10A. C. Schematic diagram of the predicted primary structure of human WNT10A (signal peptide (SP); N-terminal domain (NTD) with Helix E, Thumb hairpin containing the O-acylation site (in red) and Helix F; interface motif containing the linker region; and C-terminal domain (CTD) with Helix G and Index finger hairpin) based on the crystal structure of human WNT3 (Kantaputra and Sripathomsawat, 2011).

Fig. 2.

Expression patterns of mouse and zebrafish Wnt10a. Expression pattern of Wnt10a at bud and cap stages of tooth development in mice. Frontal sections through E13.5 and E14.5 M. A. Wnt10a is expressed at the tip of the epithelial bud. B. Wnt10a is expressed in the enamel knot. e, epithelium; ek, enamel knot; m, mesenchyme; Scale bars 0.1 mm. A and B. Reproduced/adapted (Dassule and McMahon, 1998) with permission from Elsevier. C. Expression pattern of zebrafish wnt10a at 56 hpf in the developing tooth. Transverse cryosection of 56 hpf wild-type zebrafish embryo after wnt10a in situ hybridization and p63 immunostaining, revealing strong wnt10a expression in the dental mesenchyme (dm; white arrow) and weak wnt10a expression in the surrounding p63-positive dental epithelium (de; white arrow). de, dental epithelium; dm, dental mesenchyme; n, notochord; Scale bar 20 μm. Reproduced/adapted (Benard et al., 2023) with permission from Wiley Periodicals LLC on behalf of American Association for Anatomy. D-F. Expression of Wnt10a during mouse hair follicle morphogenesis. Wnt10a in situ hybridization at E14.5 (D) and E18.5 (E and F). The dermal–epithelial junction is indicated by a dashed white line in each panel. Hair follicle placode in panel D is indicated by white brackets. Hybridization appears as red grains and nuclei are counterstained with Hoechst dye and appear blue. D. The expression of Wnt10a is slightly upregulated in the placode compared with adjacent epidermis. E. At germ stage, Wnt10a is expressed in follicular epithelial cells immediately adjacent to the dermal condensate (yellow arrows) and in the dermal condensate itself (white arrows). F. At the bulbous peg stage, Wnt10a expression decreases in the dermal papilla (white arrows) and concentrates in inner root sheath precursors (yellow arrows). The photographs in panels D-F were taken at the same magnification. A scale bar representing 20 μm is shown in panel F. DC, dermal condensate; DP, dermal papilla; IRS, inner root sheath. D-F. Reproduced/adapted (Reddy et al., 2001) with permission from Elsevier.

Fig. 3.

Mutant phenotypes in Wnt10a mutant mice and zebrafish. A. Wnt10a−/− mice have smaller molar teeth with blunted cusp formation, and presence of an ectopic molar M4 compared with control mandible at P90 (molar numbers (M#) written in yellow). B. Micro-CT analysis of mandibles from control and Wnt10a^−/− mice at 12 months old. Maxillary and mandibular molar teeth had flattened cusps, reduced size and defective root bifurcation and extension compared with littermate controls. Wnt10a^−/− mice had frequently missing molar teeth. C. Accelerated catagen following epithelial Wnt10a deletion from P9 (embryonic anagen) (photographed at P14 after hair clipping) in Krt5-rtTA tetO-Cre Wnt10a^fl/fl mice. D. Scanning electron microscope (SEM) shows fungiform (FuP, written in red letters) and filiform (FiP, written in yellow letters) papilla defects in adult global Wnt10a mutants. E. SEM reveals failure of postnatal sweat duct development in P16 Wnt10a^−/− mutant footpad. A-E. Reproduced/adapted (Xu et al., 2017) with permission from Springer Nature Limited. F. At 35 dpf (SL 13 mm), dissected ceratobranchial 5 (cb5) of zebrafish controls have fully formed alizarin red-stained mineralized teeth (only 1V, 2V, 3V, 4V, and 5V are visible in this view) while the wnt10a mutants have no teeth and an underdeveloped cb5. Arrows indicate regular teeth, arrowheads compromised or absent teeth. G. At 6 dpf, the zebrafish embryo median fin fold (MFF) of the sibling has extended while most of the mutant MFF has collapsed (arrowheads). F-G. Reproduced/adapted (Benard et al., 2023) with permission from Wiley Periodicals LLC on behalf of American Association for Anatomy. Scale bar, 50 μm (E), 100 μm (D, F), 200 μm (G), 500 μm (A) and 1 mm (B).

Fig. 4.

Clinical features associated with human WNT10A mutation. A. Panoramic radiograph of proband with oligodontia. Radiograph shows a mixed dentition stage with the presence of deciduous teeth and some permanent teeth erupted. Stars denote absence of tooth buds for teeth # 3, 4, 5, 11, 12, 13, 14, 19, 24, 29, and 30. B. Thinning hair. C. Nail dystrophy. D and E. Fissures and scaling on palms and soles. F and G. Starch-iodine sweat testing. Note brown grains on control palm indicating sweat production, and decreased sweating in patient (arrows). Insets show higher magnification of areas indicated by the lower arrow in each photograph. H and I. Smooth tongue surface A. Reproduced/adapted (Yuan et al., 2017). B-I. Reproduced/adapted (Xu et al., 2017) with permission from Springer Nature Limited.