GPSM2-GNAI Specifies the Tallest Stereocilia and Defines Hair Bundle Row Identity

Tadenev, Abigail L.D.; Akturk, Anil; Devanney, Nicholas; Mathur, Pranav Dinesh; Clark, Andrew E.; Yang, Jun; Tarchini, Basile

doi:10.1016/j.cub.2019.01.051

Cited by 63 publications

(149 citation statements)

References 52 publications

(94 reference statements)

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“…Downregulating Gαi activity in HCs with PTXa, inactivating both Gαi2 + Gαi3 or inactivating LGN resulted in profound deafness in young adults already (22)(23)(24)(25)(26). To explore the possibility that the disruption of the modiolar-pillar gradient of ribbon size is consecutive to the loss of sound-evoked synaptic activity, we turned to Myo15 sh2 mice.…”

Section: Resultsmentioning

confidence: 99%

“…LGN mutants shared stereocilia stunting and profound deafness (22)(23)(24)(25), while milder hair bundle defects and hearing loss were reported in mutant mice lacking Gαi3 (22), and these phenotypes were accentuated in conditional double Gαi2/Gαi3 mutants (25). Neither LGN nor single Gαi3 mutants recapitulate the severe PCP defects observed in PTXa-expressing HCs, presumably because of functional redundancy among Gαi proteins (18,20).…”

Section: Significancementioning

confidence: 98%

“…Gαi-LGN exclude aPKC, and the resulting compartmentalization of the HC apex influences the position of the kinocilium and the stereocilia, shaping cytoskeleton intrinsic asymmetry and possibly aligning it with tissue-wide polarity cues residing at cell-cell junctions, including core planar cell polarity (PCP) proteins (18,20,21). Moreover, LGN and Gαi are also enriched at the tips of the tallest stereocilia (22)(23)(24), making the Insc-LGN-Gαi complex a promising candidate for conveying information across compartments (23). Pertussis toxin (PTX) is well known to ADP ribosylate and block Gαi signaling, and interestingly, PTX application led to PCP defects and a deficit of kinocilium migration in HCs in cochlear cultures (20).…”

Section: Significancementioning

confidence: 99%

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Intrinsic planar polarity mechanisms influence the position-dependent regulation of synapse properties in inner hair cells

Jean

Özçete

Tarchini

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Encoding the wide range of audible sounds in the mammalian cochlea is collectively achieved by functionally diverse type I spiral ganglion neurons (SGNs) at each tonotopic position. The firing of each SGN is thought to be driven by an individual active zone (AZ) of a given inner hair cell (IHC). These AZs present distinct properties according to their position within the IHC, to some extent forming a gradient between the modiolar and the pillar IHC side. In this study, we investigated whether signaling involved in planar polarity at the apical surface can influence position-dependent AZ properties at the IHC base. Specifically, we tested the role of Gαi proteins and their binding partner LGN/Gpsm2 implicated in cytoskeleton polarization and hair cell (HC) orientation along the epithelial plane. Using high and superresolution immunofluorescence microscopy as well as patch-clamp combined with confocal Ca2+ imaging we analyzed IHCs in which Gαi signaling was blocked by Cre-induced expression of the pertussis toxin catalytic subunit (PTXa). PTXa-expressing IHCs exhibited larger CaV1.3 Ca2+-channel clusters and consequently greater Ca2+ influx at the whole-cell and single-synapse levels, which also showed a hyperpolarized shift of activation. Moreover, PTXa expression collapsed the modiolar–pillar gradients of ribbon size and maximal synaptic Ca2+ influx. Finally, genetic deletion of Gαi3 and LGN/Gpsm2 also disrupted the modiolar–pillar gradient of ribbon size. We propose a role for Gαi proteins and LGN in regulating the position-dependent AZ properties in IHCs and suggest that this signaling pathway contributes to setting up the diverse firing properties of SGNs.

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Section: Resultsmentioning

confidence: 99%

Section: Significancementioning

confidence: 98%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

Intrinsic planar polarity mechanisms influence the position-dependent regulation of synapse properties in inner hair cells

Jean

Özçete

Tarchini

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…GPSM2 interacts with the α‐subunits of G‐proteins, (including GNAI3), and modulates their activation . Additionally, GPSM2 and GNAI3 are both normally enriched in a narrow compartment at the tips of the tallest row stereocilia . A conditional deficiency of GPSM2 or GNAI3 in the mouse inner ear results in stereocilia that are shortened by approximately 40% and approximately 25%, respectively .…”

Section: Receptors Relevant To Auditory Systemmentioning

confidence: 99%

“…42 Additionally, GPSM2 and GNAI3 are both normally enriched in a narrow compartment at the tips of the tallest row stereocilia. 43,44 A conditional deficiency of GPSM2 or GNAI3 in the mouse inner ear results in stereocilia that are shortened by approximately 40% and approximately 25%, respectively. 45 Consistent with these results in mice, variants of human GPRASP2 and GPSM2 have been found to cause deafness ( Table 2).…”

Section: G-protein-coupled Receptorsmentioning

confidence: 99%

Growth factor and receptor malfunctions associated with human genetic deafness

Naz

Friedman

2019

Clinical Genetics

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A variety of different signaling pathways are necessary for development and maintenance of the human auditory system. Normal hearing allows for the detection of soft sounds within the frequency range of 20 to 20 000 Hz, but more importantly to perceive the human voice frequency band of 250 to 6000 Hz. Loss of hearing is common, and is a clinically heterogeneous disorder that can be caused by environmental factors such as exposure to loud noise, infections and ototoxic drugs. In addition, variants of hundreds of genes have been reported to disrupt processes required for hearing. Noncoding regulatory variants and variants of additional genes necessary for hearing remain to be discovered as many individuals with inherited deafness are without a genetic diagnosis, despite the advent of whole exome sequencing. Here, we discuss in detail some of these deafnesscausing variants of genes encoding a ligand or its receptor. Spotlighted in this review are three growth factor-receptor-pairs EDN3/EDNRB, HGF/MET and JAG/NOTCH, which individually are necessary for normal hearing. We also offer our perspective on unanswered questions, future challenges and potential opportunities for treatments emerging from molecular genetic and mechanistic studies of deafness due to these causes. K E Y W O R D SEDN3, EDNRB, hearing, HGF, inner ear defects, JAG, MET, NOTCH

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Espin overexpression causes stereocilia defects and provides an anti‐capping effect on actin polymerization

et al. 2022

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Stereocilia are actin-based projections of hair cells that are arranged in a step like array, in rows of increasing height, and that constitute the mechanosensory organelle used for the senses of hearing and balance. In order to function properly, stereocilia must attain precise sizes in different hair cell types and must coordinately form distinct rows with varying lengths. Espins are actin-bundling proteins that have a wellcharacterized role in stereocilia formation; loss of function mutations in Espin result in shorter stereocilia and deafness in the jerker mouse. Here we describe the generation of an Espin overexpressing transgenic mouse line that results in longer first row stereocilia and discoordination of second-row stereocilia length. Furthermore, Espin overexpression results in the misregulation of other stereocilia factors including GNAI3, GPSM2, EPS8, WHRN, and MYO15A, revealing that GNAI3 and GPSM2 are dispensable for stereocilia overgrowth. Finally, using an in vitro actin polymerization assay we show that espin provides an anti-capping function that requires both the Gactin binding WH2 domain as well as either the C-terminal F-actin binding domain or the internal xAB actin-binding domain. Our results provide a novel function for Espins at the barbed ends of actin filaments distinct from its previous known function of actin bundling that may account for their effects on stereocilia growth.

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GPSM2-GNAI Specifies the Tallest Stereocilia and Defines Hair Bundle Row Identity

Cited by 63 publications

References 52 publications

Intrinsic planar polarity mechanisms influence the position-dependent regulation of synapse properties in inner hair cells

Intrinsic planar polarity mechanisms influence the position-dependent regulation of synapse properties in inner hair cells

Growth factor and receptor malfunctions associated with human genetic deafness

Espin overexpression causes stereocilia defects and provides an anti‐capping effect on actin polymerization

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