Functional redundancy of Frizzled 3 and Frizzled 6 in planar cell polarity control of mouse hair follicles

The orientation of mouse hair follicles is controlled by the planar cell polarity (PCP) pathway. Mutations in PCP genes result in two categories of hair misorientation phenotype, randomly oriented and vertically oriented to the skin surface. Here we demonstrate that the randomly oriented hair phenotype in Frizzled 6 (Fzd6) is a partial loss of the polarity, due to the functional redundancy of another closely related Frizzled gene, Fzd3. Double knockout of Fzd3 and Fzd6 globally, or only in the skin, lead to vertically oriented hair follicles and a total loss of anterior-posterior polarity. Furthermore, we provide evidence that, contrary to the prevailing model, asymmetric localization of the Fzd6 protein is not observed in skin epithelial cells. Through transcriptome analyses and in vitro studies, we show collagen triple helix repeat containing 1 (Cthrc1) as a potential downstream effector of Fzd6, but not Fzd3. Cthrc1 binds directly to the extracellular domains of Fzd3 and Fzd6 to enhance the Wnt/PCP signaling. These results suggest that Fzd3 and Fzd6 play a redundant role in controlling the polarity of developing skin, but through non-identical mechanisms.