Repair of Noise-Induced Damage to Stereocilia F-actin Cores is Facilitated by XIRP2 271 views

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core and the cuticular plate. The damaged sites can be visualized as “gaps” in phalloidin staining of stereocilia F-actin or “tunnels” and “cracks” in cuticular plate F-actin. The enrichment of monomeric actin at stereocilia F-actin gaps, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein we show that gaps in mouse auditory hair cells are largely repaired within one week of traumatic noise exposure through the incorporation of newly synthesized actin. Additionally, we report that XIRP2 is required for the repair process and facilitates the enrichment of monomeric -actin at gaps through its LIM domain-containing C-terminus. We also expand on previous reports of noise-induced and genetic damage to the cuticular plate actin architecture. SMPX, a known deafness protein enriched in hair cells, appears to be required for the maintenance of cuticular plate integrity, likely contributing to the hearing loss we observe in Smpx knockout mice. In addition, we find that, unlike noise-induced stereocilia F-actin damage, cuticular plate damage does not recover within one week of noise exposure. This dissertation describes a novel process by which hair cells can recover from sub-lethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss. We also expand upon another form of irreversible hair cell damage, which may contribute to progressive hearing loss.

PHD (Doctor of Philosophy)

XIRP2; Hair Cell; F-actin; Stereocilia

English

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2022-04-26