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

Abstract

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 (HNF4a), which had not previously been studied in the context of cochlear response to noise, was identified as a hub of a top-ranking network. Hnf4a 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. Isoforms a3 and a12 in the cochlea were also identified. At every age examined, Hnf4a mRNA expression in the cochlear apex was similar to expression in the base. Hnf4a 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 Hnf4a upregulation was inhibited by neuropathic noise exposure in adolescence. Hnf4a silencing with shRNA transfection into auditory neuroblast cells (VOT-33) reduced cell viability, as measured with the MTT assay, suggesting that Hnf4a may be involved in SGN survival. Our results motivate future studies of HNF4a in cochlear pathophysiology, especially because HNF4a mutations and polymorphisms are associated with human diseases that may include hearing loss. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1374-1386, 2016.

View details for DOI 10.1002/dneu.22399

View details for Web of Science ID 000390008700006

View details for PubMedID 27112738