Hepatocyte Nuclear Factor-4 Alpha in Noise-Induced Cochlear Neuropathy

Noise-induced hearing loss (NIHL) is a problem of profound clinical significance and growing magnitude. Alarmingly, even moderate noise levels, previously assumed to cause only temporary shifts in auditory thresholds (temporary NIHL), are now known to cause cochlear synaptopathy and subsequent neuropathy. To uncover molecular mechanisms of this neuropathy, a network analysis of genes reported to have significantly altered expression after temporary threshold shift-inducing noise exposure was performed. The transcription factor Hepatocyte Nuclear Factor-4 alpha (HNF4 alpha), which had not previously been studied in the context of cochlear response to noise, was identified as a hub of a top-ranking network. Hnf4 alpha expression and localization using quantitative RT-PCR and in situ hybridization, respectively, were described in adolescent and adult mice exposed to neuropathic noise levels in adolescence. Iso-forms alpha 3 and alpha 12 in the cochlea were also identified. At every age examined, Hnf4 alpha mRNA expression in the cochlear apex was similar to expression in the base. Hnf4 alpha expression was evident in select cochlear cells, including spiral ganglion neurons (SGNs) and hair cells, and was significantly upregulated from 6 to 70 weeks of age, especially in SGNs. This age-related Hnf4 alpha upregulation was inhibited by neuropathic noise exposure in adolescence. Hnf4 alpha silencing with shRNA transfection into auditory neuroblast cells (VOT-33) reduced cell viability, as measured with the MTT assay, suggesting that Hnf4 alpha may be involved in SGN survival. Our results motivate future studies of HNF4 alpha in cochlear pathophysiology, especially because HNF4 alpha mutations and polymorphisms are associated with human diseases that may include hearing loss. (C) 2016 Wiley Periodicals, Inc.