Planar cell polarity signaling guides cochlear innervation.

Core planar cell polarity (PCP) proteins are linked to mechanisms of growth cone turning in response to Wnt ligands and direct the cellular organization and planar polarity of neurons, neuroepithelia and supporting cells, many of which are also the substrates along which growth cones navigate (Onishi et al., 2014; Tissir and Goffinet, 2013). Genetic manipulations in the mouse further demonstrate that PCP proteins along the migratory path can have a non-cell autonomous influence on growth cone turning (Ghimire and Deans, 2019; Ghimire et al., 2018) and neuronal migration (Davey et al., 2016; Glasco et al., 2012; Qu et al., 2010). For example, in the cochlea a distinctive 90-degree turn made by the peripheral axons of type II Spiral Ganglion Neurons (SGN) is dependent upon the PCP protein Vangl2 and the Frizzled receptors Fzd3 and Fzd6. When the corresponding genes are removed from non-neuronal supporting cells at the initial site of axon turning, the outcome of the turn is randomized (Ghimire and Deans, 2019; Ghimire et al., 2018). Together these observations demonstrate that the planar polarized development or organization of the cochlear environment through which these growth cones navigate has a substantive impact on pathfinding and axon projections. The outstanding question remains how planar polarization of cochlear supporting cells contributes to growth cone behavior, axonal trajectories and connectivity. Possibilities include the structural polarization of cells that act as physical guides, the polarized distribution of axon guidance cues within these cells, or direct intercellular PCP signaling between supporting cells and navigating growth cones. The caudal migration of facial branchiomotor neurons (FBMN) is similarly dependent upon the planar polarized distribution of PCP proteins in the neuroepithelial cell substrate along which they migrate (Davey et al., 2016). This raises the broader question of whether planar polarization of cells along a growth cone’s trajectory might contribute as a general mechanism of axon guidance, or whether this mechanism is a specialized adaptation unique to the cochlea.