Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through K _v 7.4 channel upsurge in auditory neurons and hair cells

Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO) in murine hair cells (HCs) and auditory neurons, spiral ganglion neurons (SGNs). Null-deletion of full-length REST resulted in normal HCs and SGNs development but manifested with progressive hearing loss in adulthood. We found that deletion of REST results in an increased abundance of K _v 7.4 channels at the transcript, protein, and function levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased K _v 7.4 expression and augmented K _v 7 currents; SGN’s excitability was also significantly reduced. Administration of K _v 7.4 channel activator, fasudil, recapitulated progressive hearing loss in mice.

In contrast, inhibition of the K _v 7.4 channel by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the K _v 7.4-coding gene, Kcnq4 , as a causative factor for progressive hearing loss in mice and humans. Thus, the present findings revealed that a critical homeostatic K _v 7.4 channel level is required for proper auditory functions.