Abstract
Proper structural organization of spiral ganglion (SG) innervation is crucial for normal hearing function. However, molecular mechanisms underlying the developmental formation of this precise organization remain not well understood. Here, we report in the developing mouse cochlea that deleted in colorectal cancer (Dcc) contributes to the proper organization of spiral ganglion neurons (SGNs) within the Rosenthal’s canal and of SGN projections toward both the peripheral and central auditory targets. In Dcc mutant embryos, mispositioning of SGNs occurred along the peripheral auditory pathway with misrouted afferent fibers and reduced synaptic contacts with hair cells. The central auditory pathway simultaneously exhibited similar defective phenotypes as in the periphery with abnormal exit of SGNs from the Rosenthal’s canal towards central nuclei. Furthermore, the axons of SGNs ascending into the cochlear nucleus had disrupted bifurcation patterns. Thus, Dcc is necessary for establishing the proper spatial organization of SGNs and their fibers in both peripheral and central auditory pathways, through controlling axon targeting and cell migration. Our results suggest that Dcc plays an important role in the developmental formation of peripheral and central auditory circuits, and its mutation may contribute to sensorineural hearing loss.
Highlights
Families of axon guidance molecules in the cochlea prompted us to examine the contribution of Dcc in mouse cochlear development
Our study suggests that Dcc mediates the proper organization of spiral ganglion (SG) assembly and its innervation pattern in the developing auditory circuits
We reported mispositioning of spiral ganglion neurons (SGNs) cell bodies in Slit[2] mutant mice[23]. This specific defective phenotype appears similar in Slit[2] and Dcc mutants, the developmental contexts that trigger this defect may be different between the two mutants, as the onsets of mis-migration of SGNs are not the same
Summary
Gene expression analysis of classical axon guidance molecules in mouse cochlea. Previous studies suggest involvements of classical axon guidance molecules in the developing ear[22]. Based on the known functional roles of Dcc in the developing nervous system and its highly enriched expression pattern in SGNs, we hypothesized that proper axon guidance may be provided by Dcc signaling during cochlear development To test this hypothesis, we compared the innervation pattern of SGN fibers in cochlear cross-sections between wild-type and homozygous Dcc mutant (Dcc−/−) mice. The entire z-stack images of whole-mount cochlea at E18.5 (Fig. 2J,M) were partitioned into two sets, with one consisted of planes from the apex to base of HCs (Fig. 2K,N) and the other from the base of HCs to SGN cell bodies in the Rosenthal’s canal (Fig. 2L,O) These images revealed largely normal organization of type I and type II fiber innervation of HCs in the Dcc mutant, as no aberrant fibers were observed around the HC rows (Fig. 2K,N).
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