Overactive Wnt5a signaling disrupts hair follicle polarity during mouse skin development

Area of Science:

• Developmental Biology
• Cell Biology
• Genetics

Background:

• Planar cell polarity (PCP) governs tissue organization, with Frizzled (Fzd) receptors and other proteins mediating this process in mouse hair follicles.
• The role of Wnt proteins as PCP ligands in skin development remains largely unexplored.

Purpose of the Study:

• To investigate whether Wnt proteins, specifically Wnt5a, function as PCP ligands in the developing mouse skin.
• To elucidate the signaling pathways and molecular targets involved in Wnt-mediated skin polarization.

Main Methods:

• Overexpression of Wnt5a in posterior mouse embryos to observe effects on hair follicle orientation.
• Genetic manipulation, including heterozygous loss of Fzd6 and global/posterior deletion of Wnt5a.
• Transcriptional profiling to identify Wnt5a/Fzd6 signaling targets.
• In vitro assays to assess Wnt protein activation of Fzd6 signaling.

Main Results:

• Wnt5a overexpression in posterior embryos caused local disruption of hair follicle orientation, suggesting a role in PCP.
• The Wnt5a-induced phenotype was rescued by heterozygous loss of Fzd6, indicating Wnt5a signals through Fzd6.
• Transcriptional profiling identified novel target genes regulated by Wnt5a/Fzd6 signaling in skin polarization.
• Global or posterior deletion of Wnt5a alone did not affect hair follicle orientation, implying redundancy with other Wnts.

Conclusions:

• Wnt5a functions as an orienting cue for mouse skin PCP, regulating hair follicle orientation.
• Wnt5a likely signals via Fzd6, and other Wnt proteins may cooperate with Wnt5a to ensure robust Fzd6-mediated skin polarization.
• This study establishes a novel role for Wnt5a in skin development and PCP, identifying key molecular players and pathways involved.