Topologically correct central projections of tetrapod inner ear afferents require Fzd3

Inner ear sensory afferent connections establish sensory maps between the inner ear hair cells and the vestibular and auditory nuclei to allow vestibular and sound information processing. While molecular guidance of sensory afferents to the periphery has been well studied, molecular guidance of central projections from the ear is only beginning to emerge. Disorganized central projections of spiral ganglion neurons in a Wnt/PCP pathway mutant, Prickle1, suggest the Wnt/PCP pathway plays a role in guiding cochlear afferents to the cochlear nuclei in the hindbrain, consistent with known expression of the Wnt receptor, Frizzled3 (Fzd3) in inner ear neurons. We therefore investigated the role of Wnt signaling in central pathfinding in Fzd3 mutant mice and Fzd3 morpholino treated frogs and found aberrant central projections of vestibular afferents in both cases. Ear transplantations from knockdown to control Xenopus showed that it is the Fzd3 expressed within the ear that mediates this guidance. Also, cochlear afferents of Fzd3 mutant mice lack the orderly topological organization observed in controls. Quantification of Fzd3 expression in spiral ganglion neurons show a gradient of expression with Fzd3 being higher in the apex than in the base. Together, these results suggest that a gradient of Fzd3 in inner ear afferents directs projections to the correct dorsoventral column within the hindbrain.