The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti

Yang, Tian; Kersigo, Jennifer; Jahan, Israt; Pan, Ning; Fritzsch, Bernd

doi:10.1016/j.heares.2011.03.002

Cited by 105 publications

(115 citation statements)

References 111 publications

(182 reference statements)

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“…S3). Previous studies have illustrated that the peripheral innervation of the cochlea is initially complex and branched, but matures into more simplified and straight processes during development [54][55][56]. The fine, punctate morphological appearance of the hESC-derived processes supports their immaturity, considering the morphological appearance of developing neurites in situ.…”

Section: Discussionmentioning

confidence: 81%

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

Nayagam

Edge²,

Needham³

et al. 2013

Stem Cells and Development

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In mammals, the sensory hair cells and auditory neurons do not spontaneously regenerate and their loss results in permanent hearing impairment. Stem cell therapy is one emerging strategy that is being investigated to overcome the loss of sensory cells after hearing loss. To successfully replace auditory neurons, stem cell-derived neurons must be electrically active, capable of organized outgrowth of processes, and of making functional connections with appropriate tissues. We have developed an in vitro assay to test these parameters using cocultures of developing cochlear explants together with neural progenitors derived from human embryonic stem cells (hESCs). We found that these neural progenitors are electrically active and extend their neurites toward the sensory hair cells in cochlear explants. Importantly, this neurite extension was found to be significantly greater when neural progenitors were predifferentiated toward a neural crest-like lineage. When grown in coculture with hair cells only (denervated cochlear explants), stem cell-derived processes were capable of locating and growing along the hair cell rows in an en passant-like manner. Many presynaptic terminals (synapsin 1-positive) were observed between hair cells and stem cell-derived processes in vitro. These results suggest that differentiated hESC-derived neural progenitors may be useful for developing therapies directed at auditory nerve replacement, including complementing emerging hair cell regeneration therapies.

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Section: Discussionmentioning

confidence: 81%

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

Nayagam

Edge²,

Needham³

et al. 2013

Stem Cells and Development

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“…Two lines of ideas have been proposed to explain how SGN's axon guidance is governed within the cochlea (36,37). First is the release of chemo-attractants by the target epithelium and, more recently, the interaction of membrane receptors in neurons with repulsive factors along the path of peripheral axon outgrowth.…”

Section: Discussionmentioning

confidence: 99%

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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“…Because neurotrophins regulate neuronal differentiation and survival during development (Fariñas et al 2001;Fritzsch et al 1999;Gao et al 1995;Korsching 1993;Rubel and Fritzsch 2002;Tessarollo et al 2004;Yang et al 2011), we hypothesized that exogenous NTs might be particularly effective in our developing animals, after early-onset hearing loss. In our initial study, cats were deafened as neonates, implanted unilaterally and received 10 weeks of intracochlear BDNF starting at 4 weeks of age.…”

Section: Introductionmentioning

confidence: 99%

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

Leake

Stakhovskaya

Hetherington

et al. 2013

JARO

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Both neurotrophic support and neural activity are required for normal postnatal development and survival of cochlear spiral ganglion (SG) neurons. Previous studies in neonatally deafened cats demonstrated that electrical stimulation (ES) from a cochlear implant can promote improved SG survival but does not completely prevent progressive neural degeneration. Neurotrophic agents combined with an implant may further improve neural survival. Short-term studies in rodents have shown that brain-derived neurotrophic factor (BDNF) promotes SG survival after deafness and may be additive to trophic effects of stimulation. Our recent study in neonatally deafened cats provided the first evidence of BDNF neurotrophic effects in the developing auditory system over a prolonged duration Leake et al. (J Comp Neurol 519:1526-1545. Ten weeks of intracochlear BDNF infusion starting at 4 weeks of age elicited significant improvement in SG survival and larger soma size compared to contralateral. In the present study, the same deafening and BDNF infusion procedures were combined with several months of ES from an implant. After combined BDNF + ES, a highly significant increase in SG numerical density (950 % improvement re: contralateral) was observed, which was significantly greater than the neurotrophic effect seen with ES-only over comparable durations. Combined BDNF + ES also resulted in a higher density of myelinated radial nerve fibers within the osseous spiral lamina. However, substantial ectopic and disorganized sprouting of these fibers into the scala tympani also occurred, which may be deleterious to implant function. EABR thresholds improved (re: initial thresholds at time of implantation) on the chronically stimulated channels of the implant. Terminal electrophysiological studies recording in the inferior colliculus (IC) revealed that the basic cochleotopic organization was intact in the midbrain in all studied groups. In deafened controls or after ES-only, lower IC thresholds were correlated with more selective activation widths as expected, but no such correlation was seen after BDNF + ES due to much greater variability in both measures.

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The molecular basis of making spiral ganglion neurons and connecting them to hair cells of the organ of Corti

Cited by 105 publications

References 111 publications

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

An In Vitro Model of Developmental Synaptogenesis Using Cocultures of Human Neural Progenitors and Cochlear Explants

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

Effects of Brain-Derived Neurotrophic Factor (BDNF) and Electrical Stimulation on Survival and Function of Cochlear Spiral Ganglion Neurons in Deafened, Developing Cats

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