What they found
TL;DR (qwen3.6:35b): The study identifies ESRRG as a critical regulator for normal auditory innervation and hearing, showing that its loss in mice causes early-onset hearing loss due to neuronal and synaptic defects. Despite preserved hair cells and normal outer hair cell function, the mice exhibit auditory neuropathy characterized by immature inner hair cell properties and delayed myelination.
Estrogen-related receptor gamma (ESRRG), an orphan nuclear receptor with structural homology to the classical estrogen receptors, is widely recognised as a key metabolic regulator involved in mitochondrial, synaptic, and ion-homeostatic pathways. Previous clinical studies suggest a link between ESRRG and auditory function; for example, ESRRG has been associated with susceptibility to age-related hearing loss in women and implicated in congenital hearing loss. However, the biological mechanisms by which ESRRG may mediate hearing function remain largely unknown. Here, using a combination of in vivo auditory physiological recordings, immunofluorescence analyses, single hair-cell electrophysiology, and transcriptomic approaches, we characterise the phenotype of a new inner-ear conditional Esrrg knockout (Esrrg -cKO) to investigate the role of Esrrg in the auditory system. We found that Esrrg -cKO mice of both sexes develop early-onset hearing loss, as evidenced by elevated auditory brainstem response thresholds and reduced wave 1 amplitudes from two weeks of age. These auditory deficits arise from a combination of early-onset cochlear neuronal and innervation malformations, together with inner hair cell synaptic defects and delayed myelination that persist into adulthood. Furthermore, distortion product otoacoustic emissions and endocochlear potential recordings are normal in Esrrg -cKO mice, and although sensory hair cells are preserved, IHCs retain immature biophysical properties. These findings are consistent with auditory neuropathy, and together with our comparative transcriptome analyses, indicate that Esrrg is an essential molecular driver of normal cochlear innervation and maturation.
How this applies to our program
This research highlights a distinct mechanism of hearing loss involving innervation and synaptic maturation rather than primary hair cell death, which contrasts with the typical stereocilia defects seen in STRC/DFNB16 mutations. It suggests that ESRRG-related pathways might be relevant for understanding secondary synaptic or neural complications in hair cell disorders or for developing neuroprotective therapies.
Key numbers
- Two weeks of age when auditory deficits begin
- Both sexes of mice affected
- Normal distortion product otoacoustic emissions and endocochlear potential
Links
- biorxiv_id: https://www.biorxiv.org/content/10.64898/2026.05.02.722410
- DOI: https://doi.org/10.64898/2026.05.02.722410
Connections
[source]auto-indexed 2026-05-06 by strc-lit-watch