Functional Redundancy of Frizzled 3 and Frizzled 6 in Planar Cell Polarity Control of Mouse Hair Follicles

The study demonstrated that the orientation of mouse hair follicles was controlled by the planar cell polarity (PCP) pathway, with Frizzled 3 (Fzd3) and Frizzled 6 (Fzd6) playing redundant roles. Mutations in these genes resulted in hair misorientation, with Fzd6 mutations causing partial loss of polarity due to Fzd3 compensation. Double knockout of Fzd3 and Fzd6 led to vertically oriented hair follicles and complete loss of anterior-posterior polarity. Contrary to previous models, Fzd6 did not show asymmetric localization in skin epithelial cells. Collagen triple helix repeat containing 1 (Cthrc1) was identified as a downstream effector of Fzd6, enhancing Wnt/PCP signaling by binding to Fzd3 and Fzd6. These findings indicated that Fzd3 and Fzd6 controlled skin polarity through different mechanisms.