Developmental regulation of planar cell polarity and hair-bundle morphogenesis in auditory hair cells: lessons from human and mouse genetics

AbstractIn the inner ear sensory epithelia, hair bundles atop sensory hair cells are mechanosensory apparati with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 plays a key role in planar polarization of hair cells. Par3 deletion in the inner ear resulted in defects in cochlear length, hair bundle orientation and kinocilium positioning. During PCP establishment, Par3 promotes localized Rac-Pak signaling through an interaction with Tiam1. Par3 regulates microtubule dynamics and organization, which is crucial for basal body positioning. Moreover, there is reciprocal regulation of Par3 and the core PCP molecule Vangl2. Thus, we conclude that Par3 is an effector and integrator of cell-intrinsic and tissue-level PCP signaling.One sentence summaryPar3 regulates planar polarity of auditory hair cells

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Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816333116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 4999-5008 ◽

Cited By ~ 11

Author(s):

Andre Landin Malt ◽

Zachary Dailey ◽

Julia Holbrook-Rasmussen ◽

Yuqiong Zheng ◽

Arielle Hogan ◽

...

Keyword(s):

Hair Cell ◽

Inner Ear ◽

Cell Polarity ◽

Hair Cells ◽

Planar Cell Polarity ◽

Tissue Level ◽

Hair Bundle ◽

Nucleotide Exchange ◽

Genetic Mosaic ◽

Pcp Signaling

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.

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Non-Canonical Wnt Signaling Regulates Cochlear Outgrowth and Planar Cell Polarity via Gsk3β Inhibition

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.649830 ◽

2021 ◽

Vol 9 ◽

Author(s):

Andre Landin Malt ◽

Shaylyn Clancy ◽

Diane Hwang ◽

Alice Liu ◽

Connor Smith ◽

...

Keyword(s):

Wnt Signaling ◽

Cell Polarity ◽

Planar Cell Polarity ◽

Small Gtpase ◽

Hair Bundle ◽

Apical Surface ◽

Canonical Wnt Signaling ◽

Genetic Rescue ◽

Genetic Ablation ◽

Canonical Wnt

During development, sensory hair cells (HCs) in the cochlea assemble a stereociliary hair bundle on their apical surface with planar polarized structure and orientation. We have recently identified a non-canonical, Wnt/G-protein/PI3K signaling pathway that promotes cochlear outgrowth and coordinates planar polarization of the HC apical cytoskeleton and alignment of HC orientation across the cochlear epithelium. Here, we determined the involvement of the kinase Gsk3β and the small GTPase Rac1 in non-canonical Wnt signaling and its regulation of the planar cell polarity (PCP) pathway in the cochlea. We provided the first in vivo evidence for Wnt regulation of Gsk3β activity via inhibitory Ser9 phosphorylation. Furthermore, we carried out genetic rescue experiments of cochlear defects caused by blocking Wnt secretion. We showed that cochlear outgrowth was partially rescued by genetic ablation of Gsk3β but not by expression of stabilized β-catenin; while PCP defects, including hair bundle polarity and junctional localization of the core PCP proteins Fzd6 and Dvl2, were partially rescued by either Gsk3β ablation or constitutive activation of Rac1. Our results identify Gsk3β and likely Rac1 as downstream components of non-canonical Wnt signaling and mediators of cochlear outgrowth, HC planar polarity, and localization of a subset of core PCP proteins in the cochlea.

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Auditory Hair Cells and Sensory Transduction

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.85 ◽

2017 ◽

Author(s):

Jeffrey R. Holt ◽

Gwenaëlle S.G. Géléoc

Keyword(s):

Hair Cells ◽

Water Movement ◽

Semicircular Canals ◽

Linear Acceleration ◽

Sensory Transduction ◽

Hair Bundle ◽

Apical Surface ◽

Mechanical Stimuli ◽

Auditory Hair Cells ◽

Aquatic Vertebrates

The organs of the vertebrate inner ear respond to a variety of mechanical stimuli: semicircular canals are sensitive to angular velocity, the saccule and utricle respond to linear acceleration (including gravity), and the cochlea is sensitive to airborne vibration, or sound. The ontogenically related lateral line organs, spaced along the sides of aquatic vertebrates, sense water movement. All these organs have a common receptor cell type, which is called the hair cell, for the bundle of enlarged microvilli protruding from its apical surface. In different organs, specialized accessory structures serve to collect, filter, and then deliver these physical stimuli to the hair bundles. The proximal stimulus for all hair cells is deflection of the mechanosensitive hair bundle. Hair cells convert mechanical information contained within the temporal pattern of hair bundle deflections into electrical signals, which they transmit to the brain for interpretation.

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Sensory Transduction and Adaptation in Inner and Outer Hair Cells of the Mouse Auditory System

Journal of Neurophysiology ◽

10.1152/jn.00914.2007 ◽

2007 ◽

Vol 98 (6) ◽

pp. 3360-3369 ◽

Cited By ~ 40

Author(s):

Eric A. Stauffer ◽

Jeffrey R. Holt

Keyword(s):

Hair Cells ◽

Slow Component ◽

Outer Hair Cells ◽

Fast Component ◽

Sensory Transduction ◽

Hair Bundle ◽

Sensory Cells ◽

Auditory Hair Cells ◽

Inner Hair Cells ◽

The Difference

Auditory function in the mammalian inner ear is optimized by collaboration of two classes of sensory cells known as inner and outer hair cells. Outer hair cells amplify and tune sound stimuli that are transduced and transmitted by inner hair cells. Although they subserve distinct functions, they share a number of common properties. Here we compare the properties of mechanotransduction and adaptation recorded from inner and outer hair cells of the postnatal mouse cochlea. Rapid outer hair bundle deflections of about 0.5 micron evoked average maximal transduction currents of about 325 pA, whereas inner hair bundle deflections of about 0.9 micron were required to evoke average maximal currents of about 310 pA. The similar amplitude was surprising given the difference in the number of stereocilia, 81 for outer hair cells and 48 for inner hair cells, but may be reconciled by the difference in single-channel conductance. Step deflections of inner and outer hair bundles evoked adaptation that had two components: a fast component that consisted of about 60% of the response occurred over the first few milliseconds and a slow component that consisted of about 40% of the response followed over the subsequent 20–50 ms. The rate of the slow component in both inner and outer hair cells was similar to the rate of slow adaptation in vestibular hair cells. The rate of the fast component was similar to that of auditory hair cells in other organisms and several properties were consistent with a model that proposes calcium-dependent release of tension allows transduction channel closure.

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My oh my(osin): Insights into how auditory hair cells count, measure, and shape

The Journal of Cell Biology ◽

10.1083/jcb.201512086 ◽

2016 ◽

Vol 212 (2) ◽

pp. 135-137

Author(s):

Lana M. Pollock ◽

Shih-Wei Chou ◽

Brian M. McDermott

Keyword(s):

Hair Cells ◽

Molecular Motors ◽

Hair Bundle ◽

Sensory Cells ◽

Auditory Hair Cells ◽

Cell Biol ◽

Myosin Iiia

The mechanisms underlying mechanosensory hair bundle formation in auditory sensory cells are largely mysterious. In this issue, Lelli et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201509017) reveal that a pair of molecular motors, myosin IIIa and myosin IIIb, is involved in the hair bundle’s morphology and hearing.

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