The Effects of Bcl6 KO in Mouse Model of Hearing

Abstract

Although inner and outer hair cells (IHCs and OHCs) in the inner ear are both vulnerable to noise and ototoxic drugs, IHCs are less susceptible to those insults. The molecular mechanisms of such differential vulnerability are unknown. Hair cell‐specific transcriptome analysis shows that Bcl6, a known anti‐apoptotic gene, is differentially expressed in IHCs compared to OHC with a 3‐fold difference. We hypothesize that higher expression of Bcl6 in IHCs contributes to relative resilience of IHCs to aging, ototoxic and mechanical assault. Here, we examine the role of Bcl6 on survival and differential vulnerability of IHCs and OHCs using a Bcl6 conditional knockout mouse model generated by mating the B6.Cg‐Tg(Atoh1‐cre)1Bfri/J mouse line with the B6.129S(FVB)‐Bcl6tm1.1Dent/J from Jackson Labs. Auditory Brainstem Response (ABR)‐based thresholds were determined using tone pips with frequencies between 4–50 kHz in homozygous and wild type littermate mice at postnatal ages of 30 and 90 days. Separately, application of mechanical insult through high intensity sound was used to determine if mechanical insult is sufficient to make IHCs and OHCs equally vulnerable to apoptosis. Hair cell survival and morphology from the three cochlear locations (representing apical, middle and basal turns of the cochlea) were examined using confocal microscopy. A diminished hearing threshold and loss of hair cells suggests that Bcl6 is necessary for hair cell maintenance and survival. Two lines of work are currently under way: 1) assessing changes in gene expression (transcriptomes) and identification of downstream targets of Bcl6 in hair cells using hair cells isolated and collected from three genotypes, and 2) applying ototoxic insult to mice to determine whether loss of function due to Bcl6 deletion would make IHCs equally vulnerable to noise and ototoxic insults.