The role of hair cells, cilia and ciliary motility in otolith formation in the zebrafish otic vesicle

Abstract

SUMMARYOtoliths are biomineralised structures required for the sensation of gravity, linear acceleration and sound in the zebrafish ear. Otolith precursor particles, initially distributed throughout the otic vesicle lumen, become tethered to the tips of hair cell kinocilia (tether cilia) at the otic vesicle poles, forming two otoliths. We have used high-speed video microscopy to investigate the role of cilia and ciliary motility in otolith formation. In wild-type ears, groups of motile cilia are present at the otic vesicle poles, surrounding the immotile tether cilia. A few motile cilia are also found on the medial wall, but most cilia (92-98%) in the otic vesicle are immotile. In mutants with defective cilia (iguana) or ciliary motility (lrrc50), otoliths are frequently ectopic, untethered or fused. Nevertheless, neither cilia nor ciliary motility are absolutely required for otolith tethering: a mutant that lacks cilia completely (MZovl) is still capable of tethering otoliths at the otic vesicle poles. In embryos with attenuated Notch signalling [mindbomb mutant or Su(H) morphant], supernumerary hair cells develop and otolith precursor particles bind to the tips of all kinocilia, or bind directly to the hair cells' apical surface if cilia are absent [MZovl injected with a Su(H)1+2 morpholino]. However, if the first hair cells are missing (atoh1b morphant), otolith formation is severely disrupted and delayed. Our data support a model in which hair cells produce an otolith precursor-binding factor, normally localised to tether cell kinocilia. We also show that embryonic movement plays a minor role in the formation of normal otoliths.

Peripheral Vestibular Dysfunction in Patients With Primary Ciliary Dyskinesia

“…Importantly though, we showed larger human abnormalities in otoconial function than semicircular canal function in PCD, which is consistent with previous theories on ciliary motility and otolith seeding, positioning [9] in zebrafish.…”

“…We show that saccular and utricular function is impaired in this small cohort of PCD patients. This finding suggests that ciliary structure and/or motility could contribute to otoconial organ function by impairing otoconial position or development as previous studies in zebrafish suggest [7,9].…”

“…their otolith organ [7,8]; otolith formation, positioning or nucleation might be regulated by ciliated cells known as kinocilia (tether cells) [9]. These kinocilia may serve to distribute precursor particles and localise otolith deposition for seeding and positioning.…”

Development of the inner ear

“…Surprisingly, disruption of cilia or ciliary motility results in only mild perturbations of otolith seeding and characteristic otolith defects; in the absence of cilia, otolith precursor particles adhere directly to the apical surfaces of the hair cells [40 ,41 ]. Disruption of hair cell differentiation, however (through morpholinomediated knockdown of atoh1b), results in a failure of otolith seeding [40 ]. Although these results predict the existence of a hair cell-specific otolith precursor-binding factor that becomes localised to the kinociliary tips, the identity of such a factor has so far proved elusive.…”

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

“…Motile cilia often occur in epithelial tissues to generate fluid flow, while non-motile cilia are distributed widely and are considered critical for extracellular signal reception and transduction [1,2]. Cilia play essential roles in vertebrate development, including establishment of left-right asymmetry, and brain and kidney development [3][4][5]. Disruption of cilia structure or motility is associated with a range of human disorders termed ciliopathies, such as primary ciliary dyskinesias, cystic kidney diseases and situs inversus [6][7][8][9].…”