| Description |
Sensory neurons contained within the spiral ganglia innervate the cochlea and relay sound information from the sensory receptor hair cells to central auditory targets. A subset of these, type II spiral ganglion neurons (SGN), innervate outer hair cells (OHCs) and function as auditory nociceptors by responding to noise-induced hair cell damage. The peripheral axons of type II SGNs make a characteristic turn and always project towards the base of the cochlea before making en passant synapsis with 10 or more OHCs. The mechanisms underlying the stereotypical turning of type II fibers remain poorly understood. This dissertation project focuses on the role of components of the planar cell polarity (PCP) signaling pathway in the stereotypic turning of type II SGN fibers because several studies have shown the involvement of the core PCP proteins in analogous processes including the navigation of commissural axons in the spinal cord and the polarized migration of facial branchiomotor neurons in hindbrain. Neurofilament immunostaining revealed that deleting the core PCP genes Vangl2, Celsr1, and Fzd3/Fzd6 all resulted in turning errors by type II SGN fibers in the corresponding mutants. Fzd3 also interacts genetically with Vangl2, further demonstrating that type II peripheral axon turning requires intercellular PCP signaling. Analysis of conditional gene knockout of Vangl2 and Fzd3 revealed that PCP signaling is required cell non-autonomously in the cochlea. This is in contrast to commissural axons where PCP iv signaling occurs in the growth cone. Whole-mount immunostaining reveals that VANGL2, FZD3/FZD6, and CELSR1 proteins localize asymmetrically at intercellular junctions between the basolateral surfaces of supporting cells in the organ of Corti, thus forming a polarized PCP axis that is appropriately positioned to guide axon turning through a non-autonomous manner. Finally, the polarized distribution of VANGL2 and CELSR1 is dependent on the Wnt-mediated signaling. Altogether, these data demonstrate a novel function for Wnt-PCP signaling in the developing cochlea and suggest that non-canonical WNT signaling leads to the polarized distribution of PCP proteins and intercellular PCP signaling between supporting cells of the organ of Corti, which is required to bias type II SGN turning towards the base of the cochlea. |
