Overactive Wnt5a signaling disrupts hair follicle polarity during mouse skin development

Abstract

The polarity of mouse hair follicles is controlled by the Frizzled (Fzd) receptors and other membrane planar cell polarity (PCP) proteins. Whether Wnt can act as PCP ligands in the skin remains unknown. Here, we show that overexpression of Wnt5a in the posterior part of mouse embryos causes a local disruption of hair follicle orientation. The misoriented hair follicle phenotype in Wnt5a overexpressing mice can be rescued by a heterozygous loss of Fzd6, suggesting Wnt5a is likely to signal through Fzd6. While the membrane distribution of PCP proteins seems unaffected by Wnt5a overexpression, transcriptional profiling analyses identify a set of genes as potential targets of the skin polarization program controlled by Wnt5a/Fzd6 signaling. Surprisingly, deletion of Wnt5a globally or in the posterior part of the mouse embryos does not affect hair follicle orientation. We show that multiple other Wnts are highly expressed in the developing skin. They can activate the Fzd6 signaling pathway in vitro and may act together with Wnt5a to regulate the Fzd6-mediated skin polarization. Our experiments demonstrate for the first time that Wnt5a can function as an orienting cue for mouse skin PCP.

Region-specific reversal of epidermal planar polarity in the rosette fancy mouse

“…Under this condition, hair follicle orientation was altered specifically in the posterior region of the skin, but follicles were randomized rather than reversed, as we observe in rosette mutants ( Table S4 ) ( Simonson et al, 2022 ). Furthermore, Wnt5a knockout mice do not display PCP defects in the skin, and the directional cues that orient epidermal PCP remain to be discovered ( Simonson et al, 2022 ). Whether or not posterior-specific overexpression of directional cues could reverse the axis of PCP polarity is unknown.…”

“…Whether the reversal zone of rosette mutants is patterned by CDX targets will be important to determine. The proximal promoter of human CDX2 has been used to alter gene expression specifically in the posterior region of the mouse, including the skin ( Hinoi et al, 2007 ; Chang et al, 2016 ; Simonson et al, 2022 ). The CDX2 promoter was recently used to drive posterior expression of Wnt5a, which can act as a directional cue to reorient the axis of PCP across several cell diameters ( Chu and Sokol, 2016 ; Simonson et al, 2022 ).…”

“…The proximal promoter of human CDX2 has been used to alter gene expression specifically in the posterior region of the mouse, including the skin ( Hinoi et al, 2007 ; Chang et al, 2016 ; Simonson et al, 2022 ). The CDX2 promoter was recently used to drive posterior expression of Wnt5a, which can act as a directional cue to reorient the axis of PCP across several cell diameters ( Chu and Sokol, 2016 ; Simonson et al, 2022 ). Under this condition, hair follicle orientation was altered specifically in the posterior region of the skin, but follicles were randomized rather than reversed, as we observe in rosette mutants ( Table S4 ) ( Simonson et al, 2022 ).…”

“…The CDX2 promoter was recently used to drive posterior expression of Wnt5a, which can act as a directional cue to reorient the axis of PCP across several cell diameters ( Chu and Sokol, 2016 ; Simonson et al, 2022 ). Under this condition, hair follicle orientation was altered specifically in the posterior region of the skin, but follicles were randomized rather than reversed, as we observe in rosette mutants ( Table S4 ) ( Simonson et al, 2022 ). Furthermore, Wnt5a knockout mice do not display PCP defects in the skin, and the directional cues that orient epidermal PCP remain to be discovered ( Simonson et al, 2022 ).…”

Frizzled receptors in melanomagenesis: From molecular interactions to target identification

“…Like FZDs, WNT proteins are widely expressed in many tissues. For example, the expression of 13 Wnt genes and nine Fzd genes can be detected in the developing mouse skin (21)(22)(23). The 190 possible combinations from 19 WNT ligands and 10 FZDs make the study of the paired role of WNT/FZD extremely difficult.…”