Hair Cell Mechanotransduction Regulates Spontaneous Activity and Spiral Ganglion Subtype Specification in the Auditory System

Sun, Shuohao; Babola, Travis A; Pregernig, Gabriela; So, Kathy S.; Nguyen, Matthew; Su, Shin San M.; Palermo, Adam T.; Bergles, Dwight E.; Burns, J. C.; Müller, Ulrich

doi:10.1016/j.cell.2018.07.008

Cited by 281 publications

(374 citation statements)

References 97 publications

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“…It demonstrated that new SGNs were present in all the samples of experimental groups. In addition, we checked other SGN genes such as Calb2, Pou4f1, Lypd1, Slc17a6, Slc17a7, and Pvalb , which have recently been reported in different SGN single‐cell RNA‐Seq studies . Samples #4 and #9 showed enhanced expression of all of these SGN genes compared to other samples (red arrows in Figure D).…”

Section: Resultsmentioning

confidence: 89%

“…The OHCs detect and amplify sound; this subsequently leads to the activation of IHCs, which in turn convert sound into electrical signals . Approximately 95% of spiral ganglion neuron (SGNs) are type I SGNs, which can be further subdivided into three subtypes: Type I‐A, Type I‐B, and Type I‐C, and the remaining 5% of SGNs are type II SGNs, as supported by both morphological and single‐cell transcriptome analysis . IHCs are the primary sensory cells that are connected to myelinated type I SGNs, while OHCs are innervated by unmyelinated type II SGNs.…”

Section: Introductionmentioning

confidence: 95%

“…2 Approximately 95% of spiral ganglion neuron (SGNs) are type I SGNs, which can be further subdivided into three subtypes: Type I-A, Type I-B, and Type I-C, and the remaining 5% of SGNs are type II SGNs, as supported by both morphological and single-cell transcriptome analysis. [3][4][5][6] IHCs are the primary sensory cells that are connected to myelinated type I SGNs, while OHCs are innervated by unmyelinated type II SGNs. The primary role of type I SGNs is to transmit sound-induced electrical signals from IHCs to the cochlear nucleus located in the brainstem; in contrast type II SGNs are involved in the reflexive medial olivocochlear suppression of cochlear amplification.…”

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confidence: 99%

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In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Sun

et al. 2020

FASEB j.

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Damage or degeneration of inner ear spiral ganglion neurons (SGNs) causes hearing impairment. Previous in vitro studies indicate that cochlear glial cells can be reprogrammed into SGNs, however, it remains unknown whether this can occur in vivo. Here, we show that neonatal glial cells can be converted, in vivo, into SGNs (defined as new SGNs) by simultaneous induction of Neurog1 (Ngn1) and Neurod1. New SGNs express SGN markers, Tuj1, Map2, Prox1, Mafb and Gata3, and reduce glial cell marker Sox10 and Scn7a. The heterogeneity within new SGNs is illustrated by immunostaining and transcriptomic assays. Transcriptomes analysis indicates that well reprogrammed SGNs are similar to type I SGNs. In addition, reprogramming efficiency is positively correlated with the dosage of Ngn1 and Neurod1, but declined with aging. Taken together, our in vivo data demonstrates the plasticity of cochlear neonatal glial cells and the capacity of Ngn1 and Neurod1 to reprogram glial cells into SGNs. Looking ahead, we expect that combination of Neurog1 and Neurod1 along with other factors will further boost the percentage of fully converted (Mafb+/Gata3+) new SGNs.

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Section: Resultsmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 95%

mentioning

confidence: 99%

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In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Sun

et al. 2020

FASEB j.

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“…; Sun et al . ). As explained above, such a compensatory mechanism is unlikely in Otof KOs, due to reduced spontaneous activity rates at P11 and P30.…”

Section: Discussionmentioning

confidence: 97%

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

Müller

Sonntag

Maraslioglu

et al. 2019

The Journal of Physiology

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Key points Loss of the calcium sensor otoferlin disrupts neurotransmission from inner hair cells. Central auditory nuclei are functionally denervated in otoferlin knockout mice (Otof KOs) via gene ablation confined to the periphery. We employed juvenile and young adult Otof KO mice (postnatal days (P)10–12 and P27–49) as a model for lacking spontaneous activity and deafness, respectively. We studied the impact of peripheral activity on synaptic refinement in the sound localization circuit from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO). MNTB in vivo recordings demonstrated drastically reduced spontaneous spiking and deafness in Otof KOs. Juvenile KOs showed impaired synapse elimination and strengthening, manifested by broader MNTB–LSO inputs, imprecise MNTB–LSO topography and weaker MNTB–LSO fibres. The impairments persisted into young adulthood. Further functional refinement after hearing onset was undetected in young adult wild‐types. Collectively, activity deprivation confined to peripheral protein loss impairs functional MNTB–LSO refinement during a critical prehearing period. Abstract Circuit refinement is critical for the developing sound localization pathways in the auditory brainstem. In prehearing mice (hearing onset around postnatal day (P)12), spontaneous activity propagates from the periphery to central auditory nuclei. At the glycinergic projection from the medial nucleus of the trapezoid body (MNTB) to the lateral superior olive (LSO) of neonatal mice, super‐numerous MNTB fibres innervate a given LSO neuron. Between P4 and P9, MNTB fibres are functionally eliminated, whereas the remaining fibres are strengthened. Little is known about MNTB–LSO circuit refinement after P20. Moreover, MNTB–LSO refinement upon activity deprivation confined to the periphery is largely unexplored. This leaves a considerable knowledge gap, as deprivation often occurs in patients with congenital deafness, e.g. upon mutations in the otoferlin gene (OTOF). Here, we analysed juvenile (P10–12) and young adult (P27–49) otoferlin knockout (Otof KO) mice with respect to MNTB–LSO refinement. MNTB in vivo recordings revealed drastically reduced spontaneous activity and deafness in knockouts (KOs), confirming deprivation. As RNA sequencing revealed Otof absence in the MNTB and LSO of wild‐types, Otof loss in KOs is specific to the periphery. Functional denervation impaired MNTB–LSO synapse elimination and strengthening, which was assessed by glutamate uncaging and electrical stimulation. Impaired elimination led to imprecise MNTB–LSO topography. Impaired strengthening was associated with lower quantal content per MNTB fibre. In young adult KOs, the MNTB–LSO circuit remained unrefined. Further functional refinement after P12 appeared absent in wild‐types. Collectively, we provide novel insights into functional MNTB–LSO circuit maturation governed by a cochlea‐specific protein. The central malfunctions in Otof KOs may have implications for patients with sensorineuronal hearing loss.

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“…Shear stress is elicited by the flow of blood and interstitial fluid around cancer cells. To produce transient cellular responses, mechanical stresses are sensed and transduced to generate biochemical signals via a process called mechanotransduction . This process involves mechanosensors (e.g.…”

Section: Mechanical Stressmentioning

confidence: 99%

Therapeutic targeting of cellular stress responses in cancer

Chen

Xie

2018

Thoracic Cancer

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Similar to bacteria, yeast, and other organisms that have evolved pathways to respond to environmental stresses, cancer cells develop mechanisms that increase genetic diversity to facilitate adaptation to a variety of stressful conditions, including hypoxia, nutrient deprivation, exposure to DNA‐damaging agents, and immune responses. To survive, cancer cells trigger mechanisms that drive genomic instability and mutation, alter gene expression programs, and reprogram the metabolic pathways to evade growth inhibition signaling and immune surveillance. A deeper understanding of the molecular mechanisms that underlie the pathways used by cancer cells to overcome stresses will allow us to develop more efficacious strategies for cancer therapy. Herein, we overview several key stresses imposed on cancer cells, including oxidative, metabolic, mechanical, and genotoxic, and discuss the mechanisms that drive cancer cell responses. The therapeutic implications of these responses are also considered, as these factors pave the way for the targeting of stress adaption pathways in order to slow cancer progression and block resistance to therapy.

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Hair Cell Mechanotransduction Regulates Spontaneous Activity and Spiral Ganglion Subtype Specification in the Auditory System

Cited by 281 publications

References 97 publications

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

In vivo ectopic Ngn1 and Neurod1 convert neonatal cochlear glial cells into spiral ganglion neurons

Topographic map refinement and synaptic strengthening of a sound localization circuit require spontaneous peripheral activity

Therapeutic targeting of cellular stress responses in cancer

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