A link between planar polarity and staircase-like bundle architecture in hair cells

Abstract

Sensory perception in the inner ear relies on the hair bundle, the highly polarized brush of movement detectors that crowns hair cells. We previously showed that, in the mouse cochlea, the edge of the forming bundle is defined by the 'bare zone', a microvilli-free sub-region of apical membrane specified by the Insc-LGN-Gαi protein complex. We now report that LGN and Gαi also occupy the very tip of stereocilia that directly abut the bare zone. We demonstrate that LGN and Gαi are both essential for promoting the elongation and differential identity of stereocilia across rows. Interestingly, we also reveal that total LGN-Gαi protein amounts are actively balanced between the bare zone and stereocilia tips, suggesting that early planar asymmetry of protein enrichment at the bare zone confers adjacent stereocilia their tallest identity. We propose that LGN and Gαi participate in a long-inferred signal that originates outside the bundle to model its staircase-like architecture, a property that is essential for direction sensitivity to mechanical deflection and hearing.

Gαi Proteins are Indispensable for Hearing

“…Gα i proteins and in particular the Gα i3 isoform have been previously linked to control asymmetric cell division and hair cell bundle polarity in the inner ear [16,17,19,23]. Beyond that, our present findings indicate redundant functions of Gα i2 and Gα i3 for final maturation of synapses and low frequency hearing, whereas Gα i3 is indispensable for basal cochlea hair bundle shaping, high frequency hearing, and homeostatic excitability changes in the brain.…”

“…Using various Gnai mutant mouse lines we demonstrate that deficiency for Gα i3 but not Gα i2 produces high-frequency hearing loss, whereas the absence of both isoforms results in profound deafness resembling the phenotype seen in Gpsm2 mouse mutants [19,23].…”

“…So far, Gα i3 per se has not been associated with hereditary deafness because of an assumed functional Gα i isoform redundancy for hearing. Nevertheless, we and others recently reported hearing loss in Gα i3 cKO and Atoh1-PTX mice, correlating with stereociliary elongation defects in IHCs [19,23]. It remains open whether the ubiquitously expressed Gpsm2-binding partner Gα i2 has also an impact on cochlear architecture and auditory function and whether both Gα i proteins play specific and/or redundant roles.…”

Gene, cell, and organ multiplication drives inner ear evolution

“…These mice displayed a surprisingly robust development of nearly all hair cells but in a disorganized organ of Corti. Most importantly, the stereocilia phenotypes resembled those observed in mutants of LGN and Gαi (Tarchini et al, 2016) and various Myosin mutants (Quint and Steel, 2003). Combined these data suggest that possibly the concentration and/or binding specificity of Atoh1 is an essential aspect of normal stereocilia development.…”

“…Eliminating kinocilia mediated apical reorganization results in circular polarized hair cells (Jones et al, 2008). Beyond the kinocilium as a signaling center, the apical acentric polarity development relies on several regulatory factors, such as LGN and Gαi (Tarchini et al, 2016) and Bbs8 and Ift20 (May-Simera et al, 2015) to eliminate microvilli and move the kinocilium into an acentric position and regulate the height and distribution of stereocilia to properly polarize hair cells. The end product of this incompletely understood process (Lu and Sipe, 2016; Schüler et al, 2013) is a highly polarized cell that allows mechanical stimuli to exert changes on the cell’s resting potential depending on the direction of the stimulation (Fig.…”