A Reversal in Hair Cell Orientation Organizes Both the Auditory and Vestibular Organs

Tarchini, Basile

doi:10.3389/fnins.2021.695914

Cited by 16 publications

(8 citation statements)

References 69 publications

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“…As DAPLE directly binds GNAI and dishevelled homolog (DVL2) (Fig. 1B) (29), DAPLE was proposed to couple the distinct planar polarity mechanisms that regulate cytoskeleton asymmetry in single HCs (via GPSM2-GNAI) and HC orientation along the epithelial plane [via DVL2 and other planar cell polarity (PCP) proteins ensuring intercellular communication] (25,(30)(31)(32). Many questions remain unanswered, however.…”

Section: Introductionmentioning

confidence: 99%

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

2022

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Inhibitory G proteins (GNAI/Gα i ) bind to the scaffold G protein signaling modulator 2 (GPSM2) to form a conserved polarity complex that regulates cytoskeleton organization. GPSM2 keeps GNAI in a guanosine diphosphate (GDP)-bound state, but how GPSM2-GNAI is generated or relates to heterotrimeric G protein signaling remains unclear. We find that RGS12, a GTPase-activating protein (GAP), is required to polarize GPSM2-GNAI at the hair cell apical membrane and to organize mechanosensory stereocilia in rows of graded heights. Accordingly, RGS12 and the guanine nucleotide exchange factor (GEF) DAPLE are asymmetrically co-enriched at the hair cell apical junction, and Rgs12 mouse mutants are deaf. GPSM2 and RGS12 share GoLoco motifs that stabilize GNAI(GDP), and GPSM2 outcompetes RGS12 to bind GNAI. Our results suggest that polarized GEF/GAP junctional activity might dissociate heterotrimeric G proteins, generating free GNAI(GDP) for GPSM2 at the adjacent apical membrane. GPSM2-GNAI(GDP), in turn, imparts asymmetry to the forming stereocilia to enable sensory function in hair cells.

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Section: Introductionmentioning

confidence: 99%

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

2022

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“…In order to be maximally sensitive to deflecting forces, sensory hair cells develop specific spatial orientations during late embryonic and early postnatal ages. Disruption to developmental factors influencing PCP have been shown to lead to deficits in hearing and balance [20][21][22]. Thus, we have developed the PCPA plug-in suite to automate the collection of cell polarity measurements and validated its utility extensively in cochlear and vestibular sensory epithelia.…”

Section: Introductionmentioning

confidence: 99%

PCP Auto Count: A Novel Fiji/ImageJ plug-in for automated quantification of planar cell polarity and cell counting

Stansak,

Baum,

Ghosh

et al. 2024

Preprint

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Background: During development, planes of cells give rise to complex tissues and organs. The proper functioning of some cell types is critically dependent on proper inter- and intracellular spatial orientation in regards to the overall tissue, a feature known as planar cell polarity (PCP). To study the genetic and environmental factors affecting planar cell polarity investigators must manually measure cell orientations, which is a time-consuming endeavor. Methodology: To automate cell counting and planar cell polarity data collection we developed a Fiji/ImageJ plug-in called Planar Cell Polarity Auto Count (PCPA) to analyze binary images and identify "chunks" of white pixels that contain "caves" of infiltrated black pixels. Cochleae (P4) and utricles (E17.5) from wildtype mice were immunostained for Beta-Spectrin and imaged on a confocal microscope. Images were preprocessed using existing ImageJ functionality to enhance contrast, make binary, and reduce noise. An investigator rated P4 cochlear angle measurements produced by PCPA from P4 cochlea for accuracy using a 1-5 agreement scale. For E17.5 cochlear samples, we compared mean angle measurements per utricular region derived using PCPA against manually derived angle measurements. Finally, PCPA was tested against a variety of images copied from publications examining PCP in various tissues and across various species. Results: PCPA was able to recognize and count 99.81% of cochlear hair cells (n = 1,1541 hair cells) in a sample set, and was able to obtain accurate planar cell polarity measurements for over 96% of hair cells. When allowing for a <10 degree deviation from human rater performance PCPA was able to accurately measure over 98% of cochlear hair cells. When manual angle measurements were compared to PCPA's measurements for E17.5 utricles, PCPA's mean measurements fell within -9 to +10 degrees of manually obtained mean angle measures. Qualitative examination of example images of Drosophila ommatidia, mouse ependymal cells, and mouse radial progenitors revealed a high level of accuracy for PCPA across a variety of stains, tissue types, and species. Altogether, the data suggest that the PCPA plugin suite is a robust and accurate tool for the automated collection of cell counts and PCP angle measurements.

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“…Recent work has illuminated how HCs with opposing orientations are formed during development (reviewed in (Tarchini, 2021)). Early in development all organs are polarized by core PCP proteins that are enriched asymmetrically at cell-cell junctions before HCs are born (Deans, 2013).…”

Section: Introductionmentioning

confidence: 99%

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

Ono,

Jarysta,

Hughes

et al. 2024

Preprint

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Otolith organs in the inner ear and neuromasts in the fish lateral-line harbor two populations of hair cells oriented to detect stimuli in opposing directions. The underlying mechanism is highly conserved: the transcription factor EMX2 is regionally expressed in just one hair cell population and acts through the receptor GPR156 to reverse cell orientation relative to the other population. In mouse and zebrafish, loss of Emx2 results in sensory organs that harbor only one hair cell orientation and are not innervated properly. In zebrafish, Emx2 also confers hair cells with reduced mechanosensory properties. Here, we leverage mouse and zebrafish models lacking GPR156 to determine how detecting stimuli of opposing directions serves vestibular function, and whether GPR156 has other roles besides orienting hair cells. We find that otolith organs in Gpr156 mouse mutants have normal zonal organization and normal type I-II hair cell distribution and mechano-electrical transduction properties. In contrast, gpr156 zebrafish mutants lack the smaller mechanically-evoked signals that characterize Emx2-positive hair cells. Loss of GPR156 does not affect orientation-selectivity of afferents in mouse utricle or zebrafish neuromasts. Consistent with normal otolith organ anatomy and afferent selectivity, Gpr156 mutant mice do not show overt vestibular dysfunction. Instead, performance on two tests that engage otolith organs is significantly altered - swimming and off-vertical-axis rotation. We conclude that GPR156 relays hair cell orientation and transduction information downstream of EMX2, but not selectivity for direction-specific afferents. These results clarify how molecular mechanisms that confer bi-directionality to sensory organs contribute to function, from single hair cell physiology to animal behavior.

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A Reversal in Hair Cell Orientation Organizes Both the Auditory and Vestibular Organs

Cited by 16 publications

References 69 publications

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

RGS12 polarizes the GPSM2-GNAI complex to organize and elongate stereocilia in sensory hair cells

PCP Auto Count: A Novel Fiji/ImageJ plug-in for automated quantification of planar cell polarity and cell counting

Contributions of mirror-image hair cell orientation to mouse otolith organ and zebrafish neuromast function

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