Lachgar-Ruiz, M. | Search bioRxiv

bioRxiv2026

Zfp719 is a transcription factor important for maintenance of hearing in mice

Zfp719 is a zinc finger transcription factor which, when mutated, results in hearing impairment in mice. Its closest human orthologue, OTK18, has been linked to tinnitus in large human cohorts. Here we present our investigation of the electrophysiological, structural and transcriptional phenotypes in Zfp719tm1a mutant mice. Homozygotes have near-normal hearing at two weeks old, but lose sensitivity rapidly between two and three weeks, suggesting that while Zfp719 is not required for development, it is important for maintaining hearing. Heterozygous mice exhibit progressive hearing impairment for high frequencies at older ages. We observed damaged and degenerating outer hair cells from as early as three weeks old in homozygotes. We carried out bulk RNAseq at three ages and found one gene consistently misregulated, a long non-coding RNA specific to mice, Gm15083. A better understanding of the genes regulated by Zfp719 may shed light on genes and proteins important for maintaining hearing in humans.

neuroscience↗

bioRxiv2024

Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations

Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in Mir96 all develop hearing loss, but different mutations result in different physiological, structural and transcriptional phenotypes. Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. While mice homozygous for either mutation are profoundly deaf from two weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice. Our work adds further support for the importance of the gain of novel targets in microRNA mutants, and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.

genetics↗