Dcc Mediates Functional Assembly of Peripheral Auditory Circuits

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.

Netrin-1 Confines Rhombic Lip-Derived Neurons to the CNS

“…Our results contrast with those from previous studies that reported no phenotypes in the spiral ganglion of Ntn1 hypomorphs ( Howell et al, 2007 ; Kim et al, 2016 ). These differences could be attributed to the hypomorphic nature of the Ntn1 trap/trap mice, which show a weaker phenotype: many PNs get close to their final destination ( Figures S4D and S4D’ ), and there are significantly fewer Pax6+ cells in E15.5 Ntn1 trap/trap cochleae ( Figures S4B–S4C’ ; n = 6 cochleae).…”

“…More recently, several groups have demonstrated that commissural guidance depends on ventricular- zone-derived Ntn1 accumulating in the SPR and along the commissural axons ( Dominici et al, 2017 ; Varadarajan et al, 2017 ; Yamauchi et al, 2017 ), expanding on related observations ( Charron et al, 2003 ; Kennedy et al, 2006 ). We have similarly revealed a role for SPR-localized Ntn1 in cellular confinement, providing an alternative explanation for both the reduced number of PNs in Ntn1 trap/trap mice, which was thought to reflect Ntn1’s tropic and trophic roles ( Yee et al, 1999 ), and the presence of ectopic neurons in DCC −/− cochleae, which was attributed to a mis-positioning of SGNs ( Kim et al, 2016 ). Thus, across multiple species and in multiple regions of the nervous system, Ntn1 appears to act locally to mediate its purported long-range functions.…”

“…Since PNs express DCC and fail to reach the midline in DCC −/− animals ( Fazeli et al, 1997 ; Yee et al, 1999 ), we hypothesized that Ntn1-DCC signaling underlies their confinement. Consistent with this idea, DCC −/− animals contain ectopic neurons in the cochlea that were assumed to be displaced SGNs ( Kim et al, 2016 ). We found not only that ectopic neurons in DCC −/− cochlea express Pax6, indicative of PN identity instead, but also that Pax6+ neurons are also present elsewhere in the periphery, such as in the VIIth and VIIIth nerves, demonstrating that DCC enables Ntn1-mediated confinement.…”

A non-autonomous function of the core PCP protein VANGL2 directs peripheral axon turning in the developing cochlea

“…Typically, during axon guidance, navigating growth cones interpret guidance cues in the environment through cell-surface receptors that initiate cell-signaling cascades and dynamic changes in the cytoskeleton (Bashaw and Klein, 2010;O'Donnell et al, 2009). The role of classic axon guidance cues, including semaphorin, ephrin, slit and netrin, and the neurotrophic factors neurotrophin 3 and brain-derived neurotrophic factor have been studied extensively during SGN development and patterning in the mouse (Coate et al, 2015;Defourny et al, 2013;Fritzsch et al, 1997a,b;Kim et al, 2016;Wang et al, 2013). Although these molecules make important contributions to SGN survival and migration, and towards the patterning of type I SGNs, type II SGN axon turning is not altered when the genes encoding these proteins are mutated.…”

ISL1 is necessary for auditory neuron development and contributes towards tonotopic organization

“…For instance, misplaced SGNs in the modiolus are in Ntrk2 and Ntrk3 neurotrophin receptor mutants 37 . Less severe phenotypes of misplaced SGNs have been reported for mice lacking Dcc 41 or mice with deficient Slit/Robo signaling 40 . All these reported SGN migration defects are also associated with abnormalities in projections.…”