Epithelial-mesenchymal Wnt crosstalk directs planar cell polarity in the developing cochlea.

Cochlear hair cells are precisely oriented by planar cell polarity. Wnt proteins direct planar cell polarity in vertebrates, but their roles in regulating cochlear planar cell polarity remain unclear. Here, we inhibit Wnt secretion by ablating epithelial Wntless and find shortened cochlea, mild hair cell misorientation and mislocalization of core planar cell polarity proteins, Fzd6 and Dvl2. Computational analysis predicts that epithelial Wnts (Wnt5a, Wnt7a, Wnt7b) and Wnt5a from surrounding periotic mesenchyme act on developing hair cells. Deletion of epithelial Wnt5a, Wnt7a, and Wnt7b additively shortens the cochlea without causing hair cell misorientation or Fzd6/Dvl2 mislocalization. Moreover, deletion of epithelial or both epithelial and mesenchymal Wnt5a fails to cause polarity defects. However, ablating both epithelial and mesenchymal Wntless severely shortens the cochlea and causes hair cell misorientation and mislocalized core planar cell polarity proteins. Thus, Wnts serve as global instructive cues directing cochlear outgrowth and hair cell polarization, with remarkable redundancy of distinct Wnts across epithelial and mesenchymal compartments to ensure a fail-safe developmental program.