Deletion of Oncomodulin Gives Rise to Early Progressive Cochlear Dysfunction in C57 and CBA Mice

Abstract

Ca2+ signaling is a major contributor to sensory hair cell function in the cochlea. Oncomodulin (OCM) is a Ca2+ binding protein (CaBP) preferentially expressed in outer hair cells (OHCs) of the cochlea and few other specialized cell types. Here, we expand on our previous reports and show that OCM delays hearing loss in mice of two different genetic backgrounds: CBA/CaJ and C57Bl/6J. In both backgrounds, genetic disruption of Ocm leads to early progressive hearing loss as measured by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE). In both strains, loss of Ocm reduced hearing across lifetime (hearing span) by more than 50% relative to wild type (WT). Even though the two WT strains have very different hearing spans, OCM plays a considerable and similar role within their genetic environment to regulate hearing function. The accelerated age-related hearing loss (ARHL) of the Ocm KO illustrates the importance of Ca2+ signaling in maintaining hearing health. Manipulation of OCM and Ca2+ signaling may reveal important clues to the systems of function/dysfunction that lead to ARHL.

Oncomodulin Regulates Spontaneous Calcium Signaling and Maturation of Afferent Innervation in Cochlear Outer Hair Cells

“…We generated Ocm +/+ and Ocm -/- mice with a genetically encoded calcium sensor (GCaMP6s). Similar to other studies (Climer et al, 2021; Tong et al, 2016), GCaMP6s Ocm -/- mice showed normal hearing at 3-4 weeks of age but exhibited an early onset hearing loss at 7-9 weeks. Based on our previous findings (Murtha et al, 2022), we focused this study at the onset of Ocm expression (P2).…”

“…However, by 7-9 wks, GCaMP6s Ocm -/mice showed hearing loss with higher DPOAE thresholds at 16, 22, and 32 kHz (P < 0.05, two-way ANOVA, Figure 1D). These results are consistent with other studies showing that OCM is critical for maintaining cochlear function in adult mice (Climer et al, 2021;Tong et al, 2016).…”

“…To investigate how OCM regulates spontaneous Ca 2+ activity in developing OHCs, we expressed a genetically encoded, tissue-specific Ca 2+ sensor ( Atoh1 -GCaMP6s) in Ocm wild-type ( Ocm +/+ ) and Ocm knockout ( Ocm -/- ) mice. GCaMP6s Ocm -/- mice exhibited early onset hearing loss, and their OHCs showed faster KCl-induced Ca 2+ transients than those recorded from GCaMP6s Ocm +/+ mice and other mouse strains (Climer et al, 2021; Murtha et al, 2022; Tong et al, 2016). In neonatal mice (P2), we observed spontaneous Ca 2+ activity in OHCs that was synchronized by Ca 2+ waves elicited in the greater epithelial ridge (GER).…”

Oncomodulin regulates spontaneous calcium signalling and maturation of afferent innervation in cochlear outer hair cells

“…1C). These results are consistent with other studies showing that OCM is critical for maintaining cochlear function in adult mice (Climer et al, 2021;Tong et al, 2016).…”

“…To investigate how OCM regulates spontaneous Ca 2+ activity in developing OHCs, we expressed a genetically encoded, tissue‐specific Ca 2+ sensor ( Atoh1 ‐GCaMP6s) in Ocm wild‐type ( Ocm +/+ ) and Ocm knockout ( Ocm −/− ) mice. Ocm −/− mice exhibited early onset hearing loss, and their OHCs showed faster KCl‐induced Ca 2+ transients than those recorded from Ocm +/+ mice and other mouse strains (Climer et al., 2021; Murtha et al., 2022; Tong et al., 2016). In neonatal mice (P2), we observed spontaneous Ca 2+ activity in OHCs that was synchronized by Ca 2+ waves elicited in the GER.…”