Abstract
Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed by SorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle.
Highlights
The sensory “hair” cells of the hearing and balance organs in the inner ears of vertebrates convert movements, initiated by sound waves in the cochlea or by translational or rotational motion in the vestibular system, into electrical signals
Sensory “hair” cells in the inner ear derive their name from an organised bundle of mechano-sensory “stereocilia” on their apical surface
In this paper we demonstrate disturbances of hair bundle morphology more severe than those described for mutations in other genes involved in hair bundle formation, which affect every cochlear inner hair cells (IHC), cochlear outer hair cells (OHC) and vestibular macular hair cell, with different effects on each of these hair cell types, but which does not affect the hair bundles of hair cells in the cristae
Summary
The sensory “hair” cells of the hearing and balance (vestibular) organs in the inner ears of vertebrates convert movements, initiated by sound waves in the cochlea or by translational or rotational motion in the vestibular system, into electrical signals. Fundamental to their function is the organised bundle of stiff, erect projections from their apical (luminal) surface [1] from which hair cells derive their name. Deflections of the stereocilia along the line of polarity, towards and away from the position of the kinocilium/basal body, opens and closes “mechano-transduction” channels [6], initiating hair cell responses
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