Frizzled3andFrizzled6Cooperate withVangl2to Direct Cochlear Innervation by Type II Spiral Ganglion Neurons

Abstract

Type II spiral ganglion neurons provide afferent innervation to outer hair cells of the cochlea and are proposed to have nociceptive functions important for auditory function and homeostasis. These neurons are anatomically distinct from other classes of spiral ganglion neurons because they extend a peripheral axon beyond the inner hair cells that subsequently makes a distinct 90 degree turn toward the cochlear base. As a result, patterns of outer hair cell innervation are coordinated with the tonotopic organization of the cochlea. Previously, it was shown that peripheral axon turning is directed by a nonautonomous function of the core planar cell polarity (PCP) protein VANGL2. We demonstrate using mice of either sex that Fzd3 and Fzd6 similarly regulate axon turning, are functionally redundant with each other, and that Fzd3 genetically interacts with Vangl2 to guide this process. FZD3 and FZD6 proteins are asymmetrically distributed along the basolateral wall of cochlear-supporting cells, and are required to promote or maintain the asymmetric distribution of VANGL2 and CELSR1. These data indicate that intact PCP complexes formed between cochlear-supporting cells are required for the nonautonomous regulation of axon pathfinding. Consistent with this, in the absence of PCP signaling, peripheral axons turn randomly and often project toward the cochlear apex. Additional analyses of Porcn mutants in which WNT secretion is reduced suggest that noncanonical WNT signaling establishes or maintains PCP signaling in this context. A deeper understanding of these mechanisms is necessary for repairing auditory circuits following acoustic trauma or promoting cochlear reinnervation during regenerationbased deafness therapies.

Axodendritic versus axosomatic cochlear efferent termination is determined by afferent type in a hierarchical logic of circuit formation

“…This finding reveals that the compartment in which the hair cells reside, rather than the type of hair cell (outer versus inner), determines the innervation pattern of type II afferents. This is consistent with reports that type II afferent innervation is guided by signals from supporting cells (33,(59)(60)(61)(62) and contrary to what we have found for type I afferents.…”

“…In contrast, little is currently known about what guides type II afferents. Supporting cells ensure that type II fibers turn correctly toward the base upon entering the outer compartment (30)(31)(32)(33). However, it is unclear why type II afferents pass by IHCs but fail to innervate them.…”

Development in the Mammalian Auditory System Depends on Transcription Factors

“…For example, in Prox1 mutants, type II fibers turn at random and merge into a single bundle compared to the three parallel fibers that turn toward the base in controls (Figure 3A,B; [30,56]). Furthermore, the loss of Schwann cells following Sox10 deletion results in fibers projecting beyond the target HCs (Figure 3C; [54,57,58]). Additional genes, such as the Wnt/planar cell polarity (PCP) genes, Vangl2, Fzd3, and Fzd6, have been shown to affect type II fiber guidance to OHCs [58].…”

“…Furthermore, the loss of Schwann cells following Sox10 deletion results in fibers projecting beyond the target HCs (Figure 3C; [54,57,58]). Additional genes, such as the Wnt/planar cell polarity (PCP) genes, Vangl2, Fzd3, and Fzd6, have been shown to affect type II fiber guidance to OHCs [58]. Mice in which Atoh1 was replaced by Neurog1 (Atoh1 kiNeurog1 ) showed a different inner ear innervation pattern.…”

“…Deleting Pax2 also results in the cochlear sack's prolapse into the braincase beneath the brainstem (Figure 4H; [66]). Various other genes either entirely or partially derail the process of innervation [30,51,58,82]. For example, deleting even a single neurotrophin (Bdnf or Ntf3) results in some neuronal loss and aberrant innervation of the remaining neurons' sensory epithelia [46,47].…”