Abstract
ABSTRACTSensory hair cells are susceptible to numerous insults, including certain therapeutic medications like aminoglycoside antibiotics, and hearing and balance disorders are often a dose-limiting side effect of these medications. We show that mutations in multiple genes in both the retrograde intraflagellar transport (IFT) motor and adaptor complexes lead to resistance to aminoglycoside-induced hair cell death. These mutations also lead to defects in the entry of both aminoglycosides and the vital dye FM1-43 into hair cells, both processes that depend on hair cell mechanotransduction activity. However, the trafficking of proteins important for mechanotransduction activity is not altered by these mutations. Our data suggest that both retrograde IFT motor and adaptor complex genes are playing a role in aminoglycoside toxicity through affecting aminoglycoside uptake into hair cells.
Highlights
During development, hair cells – the sensory cells of the auditory and vestibular systems – contain a single primary cilium on their apical surface known as the kinocilium
Mutations in multiple retrograde intraflagellar transport (IFT) genes lead to resistance to neomycin-induced hair cell death We had previously identified mutations in dync2h1 and wdr35, two genes important for retrograde IFT, through a forward genetic screen for mutants resistant to neomycin-induced hair cell death (Stawicki et al, 2016)
We found that another mutant identified through that screen, w151, mapped to a region on Chromosome 24 containing the retrograde intraflagellar transport gene ift140 (Fig. 1A)
Summary
Hair cells – the sensory cells of the auditory and vestibular systems – contain a single primary cilium on their apical surface known as the kinocilium. The kinocilium is lost in auditory hair cells of many species but always maintained in vestibular hair cells (Ernstson and Smith, 1986; Lim and Anniko, 1985; Tanaka and Smith, 1978). While mutations in cilia-associated genes have been found in multiple human patients with hearing loss (Delmaghani et al, 2016; Grati et al, 2015; Hearn et al, 2005; Ross et al, 2005), how the kinocilium affects mature hair cells has remained largely a mystery. Hair cells have actin-based protrusions on their apical surface known as stereocilia. The kinocilium and cilia genes have been shown to be
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