EMX2-GPR156-Gαi reverses hair cell orientation in mechanosensory epithelia

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: May 17, 2021

Abstract Hair cells detect sound, head position or water movements when their mechanosensory hair bundle is deflected. Each has an asymmetric architecture that restricts stimulus detection to a single axis. Coordinated cell orientations within sensory epithelia further tune at the organ level. Here, we identify GPR156, orphan GPCR of unknown function, as critical regulator orientation. We demonstrate transcription factor EMX2 polarizes GPR156 distribution, enabling it signal through Gαi and trigger 180° reversal in GPR156-Gαi mediated essential establish with mirror-image mouse otolith organs vestibular system zebrafish lateral line. Remarkably, also instructs auditory epithelium, despite lack organization. Overall, our work demonstrates conserved signaling integral framework builds directional responses into epithelia.

Language: Английский

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Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(3), P. 105756 - 105756

Published: Feb. 15, 2024

Heterotrimeric G proteins (Gαβγ) are molecular switches that relay signals from 7-transmembrane receptors located at the cell surface to cytoplasm. The function of these is so intimately linked heterotrimeric they named protein-coupled (GPCRs), showcasing interdependent nature this archetypical receptor-transducer axis transmembrane signaling in eukaryotes. It generally assumed activation protein occurs exclusively by action GPCRs, but idea has been challenged discovery alternative mechanisms which can propagate cell. This review will focus on a general principle operates without direct involvement GPCRs. mechanism reviewed here mediated class regulators defined containing an evolutionarily conserved sequence Gα-binding-and-activating (GBA) motif. Using best characterized with GBA motif as examples, Gα-interacting vesicle-associated (GIV)/Girdin and dishevelled-associating high frequency leucine residues (DAPLE), cover (i) extracellular cues not relayed GPCRs promote coupling motif-containing proteins, (ii) structural basis for how motifs interact Gα subunits facilitate signaling, (iii) relevance different cellular pathological processes, including cancer birth defects, (iv) strategies manipulate GBA-G experimental therapeutics purposes, development rationally engineered chemical probes.

Language: Английский

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The role of prickle proteins in vertebrate development and pathology

Molecular and Cellular Biochemistry, Journal Year: 2023, Volume and Issue: 479(5), P. 1199 - 1221

Published: June 26, 2023

Abstract Prickle is an evolutionarily conserved family of proteins exclusively associated with planar cell polarity (PCP) signalling. This signalling pathway provides directional and positional cues to eukaryotic cells along the plane epithelial sheet, orthogonal both apicobasal left–right axes. Through studies in fruit fly Drosophila , we have learned that PCP manifested by spatial segregation two protein complexes, namely Prickle/Vangl Frizzled/Dishevelled. While Vangl, Frizzled, Dishevelled been extensively studied, has largely neglected. likely because its role vertebrate development pathologies still being explored not yet fully understood. The current review aims address this gap summarizing our knowledge on cover their broad versatility. Accumulating evidence suggests involved many developmental events, contributes homeostasis, can cause diseases when expression properties are deregulated. highlights importance development, discusses implications Prickle-dependent pathology, points out blind spots or potential links regarding Prickle, which could be studied further.

Language: Английский

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Not a hair out of place: Polarizing and orienting sensory hair cells

Current topics in developmental biology/Current Topics in Developmental Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Planar cell polarity regulators in asymmetric organogenesis during development and disease

Journal of genetics and genomics/Journal of Genetics and Genomics, Journal Year: 2022, Volume and Issue: 50(2), P. 63 - 76

Published: July 6, 2022

Language: Английский

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Junctional force patterning drives both positional order and planar polarity in the auditory epithelia

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 25, 2025

Tissue function depends on the precise organisation of constituent cells. In cochlea, fidelity hearing mechanosensory hair cells being consistently surrounded by supporting addition to this positional order, auditory sensitivity crucially planar cell polarity. This is characterised alignment orientation eccentrically placed bundles each cell. These two levels order emerge simultaneously despite cellular fluxes that occur during cochlear development. However, link between tissue-scale rearrangements and intrinsic mechanisms remains unknown. By combining experimental theoretical approaches, we find a force patterning underpinning occurs through modulation phospho-type regulatory light chain non-muscle myosin II at specific cell-cell junctions epithelium. We propose control junctional mechanics vital for multi-cell-type epithelia.

Language: Английский

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Conserved and Divergent Principles of Planar Polarity Revealed by Hair Cell Development and Function

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Oct. 18, 2021

Planar polarity describes the organization and orientation of polarized cells or cellular structures within plane an epithelium. The sensory receptor hair vertebrate inner ear have been recognized as a preeminent model system for studying planar its development. This is principally because in structurally molecularly apparent therefore easy to visualize. Inner also functionally significant are mechanosensors stimulated by sound motion underlies mechanosensory mechanism, thereby facilitating auditory vestibular functions ear. Structurally, cell evident bundle actin-based protrusions from apical surface called stereocilia that necessary mechanosensation when stereociliary disrupted behavioral deficits emerge. Hair distributed between six epithelia evolved unique patterns facilitate function. Thus, specialized adaptations occurred distinguish will be described throughout this review. There three levels can visualized These intrinsic individual cells, coordinated epithelia, bipolarity; subset which bundles oriented opposite directions but remain aligned along common axis. with complement allows these levels, inter-relationships them, studied using single organism. purpose review introduce functional significance systems our contemporary understanding developmental mechanisms associated organizing at levels.

Language: Английский

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Wnt7b acts in concert with Wnt5a to regulate tissue elongation and planar cell polarity via noncanonical Wnt signaling

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(35)

Published: Aug. 22, 2024

Intercellular signaling mediated by evolutionarily conserved planar cell polarity (PCP) proteins aligns along the tissue plane and drives polarized behaviors during morphogenesis. Accumulating evidence indicates that vertebrate PCP pathway is regulated noncanonical, β-catenin-independent Wnt signaling; however, components mechanisms are incompletely understood. In mouse hearing organ, both noncanonical (ncWnt) required in developing auditory sensory epithelium to control cochlear duct elongation of resident hair cells (HCs), including shape orientation stereociliary bundle essential for sound detection. We have recently discovered a Wnt/G-protein/PI3K coordinates HC intercellular signaling. Here, we identify Wnt7b as ncWnt ligand acting concert with Wnt5a promote diverse developmental processes. cochlea, redundantly coiling elongation, polarity, asymmetric localization core Fzd6 Dvl2. Mechanistically, Wnt5a/Wnt7b-mediated promotes membrane recruitment Daple, nonreceptor guanine nucleotide exchange factor Gαi, activates PI3K/AKT ERK signaling, which localization. Thus, pathways distinct mutant phenotypes components, suggesting they act separate, parallel nonoverlapping functions NcWnt reinforces regulating trafficking PCP-specific Frizzled receptors.

Language: Английский

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Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 31, 2021

It has become evident that activation of heterotrimeric G-proteins by cytoplasmic proteins are not G-protein-coupled receptors (GPCRs) plays a role in physiology and disease. Despite sharing the same biochemical guanine nucleotide exchange factor (GEF) activity as GPCRs vitro, mechanisms which these trigger G-protein-dependent signaling cells have been elucidated. Heterotrimeric can give rise to two active species, Gα-GTP dissociated Gβγ, with different downstream effectors, but how non-receptor GEFs affect levels species is known. Here, systematic comparison three unrelated GEF vitro (GIV/Girdin, AGS1/Dexras1, Ric-8A) revealed high divergence their contribution generating free Gβγ directly measured live-cell biosensors. These findings demonstrate fundamental differences receptor G-protein activators promote despite similar activities vitro.

Language: Английский

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Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea

Development, Journal Year: 2020, Volume and Issue: unknown

Published: Jan. 1, 2020

Planar cell polarity (PCP) proteins localize asymmetrically to instruct within the tissue plane, with defects leading deformities of limbs, neural tube, and inner ear. Wnt are evolutionarily conserved cues, yet mutants display variable PCP defects, thus how Wnts regulate remains unresolved. Here, we used developing cochlea as a model system show that secreted through polarizing specific subset proteins. Conditional deletion Wntless or Porcupine, both essential for secretion Wnts, caused misrotated sensory cells shortened cochlea-both hallmarks defects. Wntless-deficient cochleae lacked polarized components Dishevelled1/2 Frizzled3/6, while other (Vangl1/2, Celsr1, Dishevelled3) remained localized. We identified seven paralogues, including major regulator Wnt5a, which was surprisingly dispensable planar polarization in cochlea. Finally, Vangl2 haploinsufficiency markedly accentuated Together, our study indicates coordinate ensure proper during development.

Language: Английский

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