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Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear.

ABSTRACT: Degeneration of cochlear sensory neurons is an important cause of hearing loss, but the mechanisms that maintain the survival of adult cochlear sensory neurons are not clearly defined. We now provide evidence implicating the neuregulin (NRG)-erbB receptor signaling pathway in this process. We found that NRG1 is expressed by spiral ganglion neurons (SGNs), whereas erbB2 and erbB3 are expressed by supporting cells of the organ of Corti, suggesting that these molecules mediate interactions between these cells. Transgenic mice in which erbB signaling in adult supporting cells is disrupted by expression of a dominant-negative erbB receptor show severe hearing loss and 80% postnatal loss of type-I SGNs without concomitant loss of the sensory cells that they contact. Quantitative RT-PCR analysis of neurotrophic factor expression shows a specific downregulation in expression of neurotrophin-3 (NT3) in the transgenic cochleas before the onset of neuronal death. Because NT3 is critical for survival of type I SGNs during development, these results suggest that it plays similar roles in the adult. Together, the data indicate that adult cochlear supporting cells provide critical trophic support to the neurons, that survival of postnatal cochlear sensory neurons depends on reciprocal interactions between neurons and supporting cells, and that these interactions are mediated by NRG and neurotrophins.

SUBMITTER: Stankovic K

PROVIDER: S-EPMC6729966 | biostudies-literature | 2004 Oct

REPOSITORIES: biostudies-literature

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Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear.

Stankovic Konstantina K Rio Carlos C Xia Anping A Sugawara Mitsuru M Adams Joe C JC Liberman M Charles MC Corfas Gabriel G

The Journal of neuroscience : the official journal of the Society for Neuroscience 20041001 40

Degeneration of cochlear sensory neurons is an important cause of hearing loss, but the mechanisms that maintain the survival of adult cochlear sensory neurons are not clearly defined. We now provide evidence implicating the neuregulin (NRG)-erbB receptor signaling pathway in this process. We found that NRG1 is expressed by spiral ganglion neurons (SGNs), whereas erbB2 and erbB3 are expressed by supporting cells of the organ of Corti, suggesting that these molecules mediate interactions between ...[more]

PMID: 15470130

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Project description:The Delta/Notch‑like epidermal growth factor‑related receptor (DNER) serves an important role in the developing central nervous system. However, the actions of DNER in the development of the spiral ganglion in the inner ear have yet to be elucidated. Wild‑type C57BL/6 mice were housed and time‑mated for use in the present study. Primary neuronal cultures were prepared using spiral ganglion progenitors isolated from the modiolus of postnatal day 1 (P1) mice. DNER recombinant lentiviral vectors were constructed and transfected into the cultured primary neurons. The relative proportion of differentiated neurons and the length of their neurites were evaluated using microscopy. The results of the present study demonstrated that DNER was expressed in spiral ganglion neurons (SGNs) that exhibited significant polarity in the early differentiation stages; DNER expression gradually decreased until the polarity was lost on week 35. The in vitro expression of DNER was revealed to be similar to that in vivo. When DNER expression was silenced using RNA interference, the polarity of the differentiated neurons was altered and they exhibited significantly reduced dendritic length. In addition, the proportion of bipolar neurons was decreased compared with the control group. Furthermore, the expression of α‑synuclein and the GluR2/3 subunits of the α‑amin‑o‑3‑hydroxy‑5‑methyl‑4-isoxazolepropionic acid glutamate receptor were also reduced in cultured neurons in which DNER was silenced. Notch1 was co‑expressed with DNER in SGNs isolated from P1 mice. The indirect Notch inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]‑S‑phenylglycine t‑butyl ester also affected the polarity and the formation of protrusions, and reduced the expression of DNER and glial fibrillary acidic protein in SGNs. In conclusion, the present study demonstrated that DNER was expressed in SGNs and appeared to be involved in the mechanisms underlying neuronal polarity and neuritogenesis, via a Notch‑dependent signaling pathway.

Dataset Information

Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear.

Publications

Survival of adult spiral ganglion neurons requires erbB receptor signaling in the inner ear.

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