Abstract
Spiral ganglion neurons (SGNs) are primary auditory neurons in the spiral ganglion that transmit sound information from the inner ear to the brain and play an important role in hearing. Impairment of SGNs causes sensorineural hearing loss (SNHL), and it has been thought until now that SGNs cannot be regenerated once lost. Furthermore, no fundamental therapeutic strategy for SNHL has been established other than inserting devices such as hearing aids and cochlear implants. Here we show that the mouse spiral ganglion contains cells that are able to proliferate and indeed differentiate into neurons in response to injury. We suggest that SRY-box transcription factor 2/SRY-box transcription factor 10–double-positive (Sox2/Sox10–double-positive) Schwann cells sequentially started to proliferate, lost Sox10 expression, and became neurons, although the number of new neurons generated spontaneously was very small. To increase the abundance of new neurons, we treated mice with 2 growth factors in combination with valproic acid, which is known to promote neuronal differentiation and survival. This treatment resulted in a dramatic increase in the number of SGNs, accompanied by a partial recovery of the hearing loss induced by injury. Taken together, our findings offer a step toward developing strategies for treatment of SNHL.
Highlights
Spiral ganglion (SG) neurons (SGNs) are the primary auditory neurons and play a critical role in transmitting auditory information from sensory hair cells to the brain [1]
The adult mouse SG is mostly composed of quiescent SGNs and Schwann cells, both of which are nonproliferative under physiological conditions [6, 12, 25], it has been reported that Schwann cells can proliferate after injury [14, 26]
A previous study suggested that Sox2, as well as SRY-box transcription factor 10 (Sox10), can be used as a Schwann cell marker in the adult mouse SG and that injury-associated proliferating cells become Schwann cells but not SGNs [14]
Summary
Spiral ganglion (SG) neurons (SGNs) are the primary auditory neurons and play a critical role in transmitting auditory information from sensory hair cells to the brain [1]. SGNs are predominantly bipolar neurons, and their development in mice begins around embryonic day (E) 9 in the otocyst [6]. Neural stem/precursor cells (NS/PCs) differentiate and become postmitotic in the cochlear duct around E12, migrate a short distance from the otocyst to the SG by E14, send fibers to the organ of Corti, and eventually reach the inner/outer hair cells around E16 [7, 8]. Functional hearing begins to occur at postnatal day (P) 11, and the cochleae acquire adult-type morphology with terminally differentiated and quiescent cells by P20 [13]. It has been reported that Schwann cells even in the adult mouse SG can proliferate in response to auditory system injury; these proliferative cells do not differentiate into neurons, and there is no improvement in hearing [14]
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