Otic Mesenchyme Cells Regulate Spiral Ganglion Axon Fasciculation through a Pou3f4/EphA4 Signaling Pathway

Coate, Thomas M.; Raft, Steven; Zhao, Xin; Ryan, Aimee K.; Crenshaw, E. Bryan; Kelley, Matthew W.

doi:10.1016/j.neuron.2011.10.029

Cited by 89 publications

(126 citation statements)

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“…This model is compatible with recent data showing that, during the anterior stage of fibre outgrowth and extension to the OC, EphA4 is expressed in the otic mesenchyme and interacts with ephrin-B2 on developing SGN axons 25 . Indeed, it can be suggested that, at late embryonic stages, EphA4 promotes SGN fasciculation through ephrin-B2 reverse signalling; once afferents have reached the OC, EphA4 (expressed in type I SGNs) forward signalling controls target specification through interaction with ephrin-A5 (expressed by OHCs) at early postnatal stages.…”

Section: Discussionsupporting

confidence: 93%

“…Indeed, it can be suggested that, at late embryonic stages, EphA4 promotes SGN fasciculation through ephrin-B2 reverse signalling; once afferents have reached the OC, EphA4 (expressed in type I SGNs) forward signalling controls target specification through interaction with ephrin-A5 (expressed by OHCs) at early postnatal stages. Importantly, this hypothesis of a double role for EphA4 is supported by the fact that, in addition to be expressed in the otic mesenchyme, EphA4 mRNA was also found in the SG 25 .…”

Section: Discussionmentioning

confidence: 90%

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Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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Hearing requires an optimal afferent innervation of sensory hair cells by spiral ganglion neurons in the cochlea. Here we report that complementary expression of ephrin-A5 in hair cells and EphA4 receptor among spiral ganglion neuron populations controls the targeting of type I and type II afferent fibres to inner and outer hair cells, respectively. In the absence of ephrin-A5 or EphA4 forward signalling, a subset of type I projections aberrantly overshoot the inner hair cell layer and invade the outer hair cell area. Lack of type I afferent synapses impairs neurotransmission from inner hair cells to the auditory nerve. By contrast, radial shift of type I projections coincides with a gain of presynaptic ribbons that could enhance the afferent signalling from outer hair cells. Ephexin-1, cofilin and myosin light chain kinase act downstream of EphA4 to induce type I spiral ganglion neuron growth cone collapse. Our findings constitute the first identification of an Eph/ephrin-mediated mutual repulsion mechanism responsible for specific sorting of auditory projections in the cochlea.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 90%

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

et al. 2013

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“…Each bundle is formed of fibers with similar frequency tuning. This distinct fasciculation pattern is more evident at the base/mid region of the cochlea than at the apex (17). SGN axons in Ror1 mutant cochlea failed to fasciculate correctly, arranging in less condensed bundles (Fig.…”

Section: Auditory Neuropathy and Inner Ear Anatomic Defects In Ror1 Mmentioning

confidence: 92%

“…To investigate the effect of Ror1 deficiency on the neuronal phenotype within the organ of Corti, we analyzed the total innervation pattern (z-stack images) in P5 whole-mount surface preparations of cochlea labeled with anti-neurofilament antibody and counterstained with phalloidin. In cochlear development, spiral ganglion neurons (SGNs) project peripheral axons through surrounding mesenchyme cells, forming dense fascicles before penetrating the sensory epithelium (17). Each bundle is formed of fibers with similar frequency tuning.…”

Section: Auditory Neuropathy and Inner Ear Anatomic Defects In Ror1 Mmentioning

confidence: 99%

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ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Diaz‐Horta

Abad

Sennaroḡlu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hair cells of the inner ear, the mechanosensory receptors, convert sound waves into neural signals that are passed to the brain via the auditory nerve. Little is known about the molecular mechanisms that govern the development of hair cell-neuronal connections. We ascertained a family with autosomal recessive deafness associated with a common cavity inner ear malformation and auditory neuropathy. Via whole-exome sequencing, we identified a variant (c.2207G>C, p.R736T) in ROR1 (receptor tyrosine kinase-like orphan receptor 1), cosegregating with deafness in the family and absent in ethnicitymatched controls. ROR1 is a tyrosine kinase-like receptor localized at the plasma membrane. At the cellular level, the mutation prevents the protein from reaching the cellular membrane. In the presence of WNT5A, a known ROR1 ligand, the mutated ROR1 fails to activate NF-κB. Ror1 is expressed in the inner ear during development at embryonic and postnatal stages. We demonstrate that Ror1 mutant mice are severely deaf, with preserved otoacoustic emissions. Anatomically, mutant mice display malformed cochleae. Axons of spiral ganglion neurons show fasciculation defects. Type I neurons show impaired synapses with inner hair cells, and type II neurons display aberrant projections through the cochlear sensory epithelium. We conclude that Ror1 is crucial for spiral ganglion neurons to innervate auditory hair cells. Impairment of ROR1 function largely affects development of the inner ear and hearing in humans and mice.deafness | whole-exome sequencing | inner ear | innervation | NF-κB S ensorineural hearing loss (SNHL) is diagnosed in approximately 1 per 500 newborns (1). A genetic etiology is present in more than half of the cases. Inner ear anomalies (IEAs), demonstrated with computerized tomography or magnetic resonance imaging, are associated with SNHL in about one-third of individuals (2). Although IEAs can be diagnosed in patients with other clinical manifestations, such as those seen in Waardenburg [Mendelian Inheritance in Man (MIM) 193500], Pendred (MIM 274600), or BOR (MIM 113650) syndromes, the majority of cases fall into the category of nonsyndromic deafness. Despite recent progress in identifying genes that determine many forms of hearing loss (hereditaryhearingloss.org/), the genetic basis of IEAs in humans remains largely unknown.The inner ear is a complex organ that is built from a simple structure, referred to as the otocyst, through a series of morphogenetic events. Roughly, it consists of a dorsal vestibular and a ventral auditory component (3). Studies in model organisms have identified a number of genes that play roles in proper development of the inner ear. Mouse models have been particularly relevant because the anatomy and physiology of the murine auditory system are similar to those of humans. Mutations in human orthologs of many of these genes have been reported to cause deafness in humans as well (4).Next-generation sequencing technologies have allowed rapid identification of novel human deafness genes. Appro...

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Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System

Lou,

Ma,

et al. 2024

Advanced Science

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The physiological interactions between the peripheral and central auditory systems are crucial for auditory information transmission and perception, while reliable models for auditory neural circuits are currently lacking. To address this issue, mouse and human neural pathways are generated by utilizing a carbon nanotube nanofiber system. The super‐aligned pattern of the scaffold renders the axons of the bipolar and multipolar neurons extending in a parallel direction. In addition, the electrical conductivity of the scaffold maintains the electrophysiological activity of the primary mouse auditory neurons. The mouse and human primary neurons from peripheral and central auditory units in the system are then co‐cultured and showed that the two kinds of neurons form synaptic connections. Moreover, neural progenitor cells of the cochlea and auditory cortex are derived from human embryos to generate region‐specific organoids and these organoids are assembled in the nanofiber‐combined 3D system. Using optogenetic stimulation, calcium imaging, and electrophysiological recording, it is revealed that functional synaptic connections are formed between peripheral neurons and central neurons, as evidenced by calcium spiking and postsynaptic currents. The auditory circuit model will enable the study of the auditory neural pathway and advance the search for treatment strategies for disorders of neuronal connectivity in sensorineural hearing loss.

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Otic Mesenchyme Cells Regulate Spiral Ganglion Axon Fasciculation through a Pou3f4/EphA4 Signaling Pathway

Cited by 89 publications

References 59 publications

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

Ephrin-A5/EphA4 signalling controls specific afferent targeting to cochlear hair cells

ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice

Integration of Functional Human Auditory Neural Circuits Based on a 3D Carbon Nanotube System

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