The GPSM2/LGN GoLoco motifs are essential for hearing

Bhonker, Yoni; Abu‐Rayyan, Amal; Ushakov, Kathy; Amir-Zilberstein, Liat; Shivatzki, Shaked; Yizhar-Barnea, Ofer; Elkan-Miller, Tal; Tayeb-Fligelman, Einav; Kim, Sun Myoung; Landau, Meytal; Kanaan, Moien; Chen, Ping Helen; Matsuzaki, Fumio; Sprinzak, David; Avraham, Karen B.

doi:10.1007/s00335-015-9614-7

Cited by 34 publications

(48 citation statements)

References 56 publications

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“…LGN and Gαi colocalize at the tips of stereocilia in the first row Insc-LGN-Gαi are planar polarized in murine cochlear post-mitotic HCs from embryonic day (E) 15.0 (Bhonker et al, 2016;Ezan et al, 2013;Tarchini et al, 2013), labeling and expanding the bare zone (Tarchini et al, 2013). At E16.5, we found that LGN and Gαi become enriched in a second apical compartment: the tips of developing stereocilia in inner hair cells (IHCs) (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…LGN or Gαi inactivation leads to disorganization of stereocilia distribution at the HC apical membrane (Bhonker et al, 2016;Ezan et al, 2013;Tarchini et al, 2013), which we interpreted to be the result of defective bare zone specification and expansion (Tarchini et al, 2013). Prompted by LGN-Gαi localization at their tips, we undertook a detailed analysis of stereocilia morphology during development.…”

Section: Resultsmentioning

confidence: 99%

“…Stunted stereocilia are a likely cause for near-complete deafness, and could be the etiology of hereditary hearing loss reported in multiple families with recessive mutations in LGN/GPSM2 (Doherty et al, 2012;Walsh et al, 2010;Yariz et al, 2012). In addition, planar polarity defects and abnormal stereocilia distribution could also play a role (Bhonker et al, 2016;Ezan et al, 2013;Tarchini et al, 2013). Direct binding between LGN and Gαi is essential for proper bundle morphogenesis and hearing, as suggested by a recent study using a mutant in which LGN lacks the Goloco motifs that mediate its interaction with Gαi (Bhonker et al, 2016).…”

Section: Stereocilia Stunting In Absence Of Lgn-gαi Coincides With Prmentioning

confidence: 99%

“…In addition, planar polarity defects and abnormal stereocilia distribution could also play a role (Bhonker et al, 2016;Ezan et al, 2013;Tarchini et al, 2013). Direct binding between LGN and Gαi is essential for proper bundle morphogenesis and hearing, as suggested by a recent study using a mutant in which LGN lacks the Goloco motifs that mediate its interaction with Gαi (Bhonker et al, 2016). Of note, Lgn and Atoh1-Cre; PTXa cochleas are still able to incorporate the FM1-43 dye, and the Cdh23 protein can still be detected near stereocilia tips in mature Lgn mutants, suggesting that LGN-Gαi do not directly affect mechanosensory channels or tip-links (Fig.…”

Section: Stereocilia Stunting In Absence Of Lgn-gαi Coincides With Prmentioning

confidence: 99%

“…Before a marked staircase pattern and tip-links arise postnatally in the mouse cochlea, 'core' planar cell polarity (PCP) proteins that are asymmetrically enriched at cell-cell junctions ensure uniform bundle orientation across HCs (May-Simera and Kelley, 2012). Furthermore, recent studies have clarified that planar asymmetry of the cytoskeleton in each HC (which is manifested, for example, by the V-shaped or semi-circular edge of the bundle and the off-center position of the kinocilium) depends on ciliary proteins, small GTPases and the Insc-LGN-Gαi complex (Bhonker et al, 2016;Ezan et al, 2013;Grimsley-Myers et al, 2009;Jones et al, 2008;Sipe and Lu, 2011;Tarchini et al, 2013). As the staircase pattern of the hair bundle is effectively a planar asymmetry in stereocilia height, we investigate here whether cell-intrinsic planar polarity signals could participate in its establishment.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Stereocilia Stunting In Absence Of Lgn-gαi Coincides With Prmentioning

confidence: 99%

Section: Stereocilia Stunting In Absence Of Lgn-gαi Coincides With Prmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization

Tadenev

Tarchini

2017

Advances in Experimental Medicine and Biology

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Mitosis is a process requiring strict spatial organization of cellular components. In particular, the orientation of the mitotic spindle with respect to the tissue defines the division plane. In turn, the orientation of cell division can regulate tissue morphology or the fate of daughter cells. While we have learned much about the mechanisms of mitotic spindle orientation, recent studies suggest that the proteins implicated can also play important roles in post-mitotic cells. Interestingly, post-mitotic protein function often involves polarizing the cell cytoskeleton during differentiation, mirroring its ability to orient the mitotic spindle during division. This review focuses on alternative functions of the spindle orientation machinery after division, when the cell undergoes a specialization process associated with differentiation or mature function, and discusses diseases associated to those alternative functions.

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Fluorescence polarization assays to measure interactions between Gα subunits of heterotrimeric G proteins and regulatory motifs

Maziarz

Garcia‐Marcos

2017

Methods in Cell Biology

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Fluorescence polarization (FP) is a simple and sensitive method allowing for the quantification of interactions between proteins and fluorescently-tagged small molecules like peptides. Heterotrimeric G proteins are critical signal transducing molecules and their activity is controlled by a complex network of regulatory proteins. Some of these regulators have defined short motifs (<40 amino acids) that are sufficient to bind G proteins and subsequently modulate their activity. For these cases, FP represents a robust and quantitative method to characterize the G protein-regulator interaction. Here we describe FP assays in a 384-well plate format to quantify interactions between Gα subunits of heterotrimeric G proteins and peptides corresponding to the Gα Binding and Activating (GBA) or GoLoco motifs, which are present in some proteins with Guanine nucleotide Exchange (GEF) (e.g., GIV/ Girdin) or Guanine nucleotide Dissociation Inhibitor (GDI) (e.g., RGS12) activity, respectively. This assay can be used to determine equilibrium dissociation constants, characterize the impact of single amino acid point mutations on the Gα-peptide interaction and is suitable for high-throughput screening.

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The GPSM2/LGN GoLoco motifs are essential for hearing

Cited by 34 publications

References 56 publications

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

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

The Spindle Orientation Machinery Beyond Mitosis: When Cell Specialization Demands Polarization

Fluorescence polarization assays to measure interactions between Gα subunits of heterotrimeric G proteins and regulatory motifs

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