Inhibitory G proteins play multiple roles to polarize sensory hair cell morphogenesis DOI Open Access
Amandine Jarysta, Abigail L. D. Tadenev, Matthew Day

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 25, 2023

Inhibitory G alpha (GNAI or Gαi) proteins are critical for the polarized morphogenesis of sensory hair cells and hearing. The extent nature their actual contributions remains unclear, however, as previous studies did not investigate all GNAI included non-physiological approaches. Pertussis toxin can downregulate functionally redundant GNAI1, GNAI2, GNAI3 GNAO proteins, but may also induce unrelated defects. Here we directly systematically determine role(s) each individual protein in mouse auditory cells. GNAI2 similarly at cell apex with binding partner GPSM2, whereas GNAI1 detected. In

Language: Английский

Myosin-based nucleation of actin filaments contributes to stereocilia development critical for hearing DOI Creative Commons
Zane G. Moreland,

Fangfang Jiang,

Carlos Aguilar

et al.

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

Published: Jan. 22, 2025

Assembly of actin-based stereocilia is critical for cochlear hair cells to detect sound. To tune their mechanosensivity, form bundles composed graded rows ascending height, necessitating the precise control actin polymerization. Myosin 15 (MYO15A) drives bundle development by delivering proteins growing that regulate polymerization via an unknown mechanism. Here, we show MYO15A itself nucleation-promoting factor. Moreover, a deafness-causing mutation in actin-binding interface inhibits nucleation activity but still preserves some movement on filaments vitro and partial trafficking vivo. Stereocilia fail elongate correctly this mutant mouse, providing evidence MYO15A-driven contributes biogenesis. Our work shows addition generating force motility, ATPase domain can directly disrupting promote cytoskeletal disease, such as hearing loss.

Language: Английский

Citations

1
A Myosin Nanomotor Essential for Stereocilia Maintenance Expands the Etiology of Hereditary Hearing Loss DFNB3 DOI Creative Commons

Ghazaleh Behnammanesh,

Abigail K. Dragich,

Xiayi Liao

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

ABSTRACT Cochlear hair cells transduce sound using stereocilia, and disruption to these delicate mechanosensors is a significant cause of hearing loss. Stereocilia architecture dependent upon the nanomotor myosin 15. A short isoform (MYO15A-2) drives stereocilia development by delivering an elongation-promoting complex (EC) tips, alternatively spliced long (MYO15A-1) tunes postnatal size in shorter which possess mechanosensitive ion channels. Disruption functions causes two distinct pathologies, underly human autosomal recessive non-syndromic loss DFNB3. Here, we characterize new isoform, MYO15A-3, that increases expression as developmental MYO15A-2 wanes reciprocally. We show critical EC initially delivered MYO15A-2, followed handover continues deliver EC. In Myo15a-3 mutant mouse, develop normally with correct targeting, but lack postnatally do not maintain their adult architecture, leading progressive conclude MYO15A-3 delivers are both required integrity. Our results add spectrum pathology underlying DFNB3 reveal molecular mechanisms necessary for resilient during life.

Language: Английский

Citations

1
Murine cochlear damage models in the context of hair cell regeneration research DOI
Ayse Maraslioglu-Sperber, Fabian Blanc, Stefan Heller

et al.

Hearing Research, Journal Year: 2024, Volume and Issue: 447, P. 109021 - 109021

Published: April 27, 2024

Language: Английский

Citations

6
The actin cytoskeleton in hair bundle development and hearing loss DOI Creative Commons
Jinho Park, Jonathan E. Bird

Hearing Research, Journal Year: 2023, Volume and Issue: 436, P. 108817 - 108817

Published: May 26, 2023

Language: Английский

Citations

12
Origin and evolution of microvilli DOI Creative Commons
Mylan Ansel, Kausthubh Ramachandran, G.K. Dey

et al.

Biology of the Cell, Journal Year: 2024, Volume and Issue: 116(11)

Published: Sept. 5, 2024

Abstract Background Information Microvilli are finger‐like, straight, and stable cellular protrusions that filled with F‐actin present a stereotypical length. They in broad range of cell types across the animal tree life mediate several fundamental functions, including nutrient absorption, photosensation, mechanosensation. Therefore, understanding origin evolution microvilli is key to reconstructing form function. Here, we review current state knowledge on perform bioinformatic survey conservation genes encoding microvillar proteins animals their unicellular relatives. Results We first detailed description mammalian based two well‐studied examples, brush border enterocytes stereocilia hair cells. also broader diversity discuss similarities differences between filopodia. Based our coupled carefully reconstructed molecular phylogenies, reconstitute order evolutionary appearance proteins. document stepwise assembly “molecular toolkit” notable bursts innovation at nodes: last common filozoan ancestor (correlated distinct from filopodia) choanozoan emergence inter‐microvillar adhesions). Conclusion Significance conclude scenario for filopodia‐like ancestral structures precursors animals.

Language: Английский

Citations

4
mTORC2 Regulates Actin Polymerization in Auditory Cells DOI Open Access
Marcelo Lanz, Maurizio Cortada, Lu Yu

et al.

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(2)

Published: Feb. 1, 2025

Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details how mTORC2 regulates intracellular processes in sensory cells have not yet been clarified. To further elucidate the role cells, we generated a Rictor knockout line from HEI-OC1 cells. mTORC2-deficient exhibited significant alterations actin cytoskeleton morphology decreased proliferation rates. Additionally, observed reduction phosphorylation protein kinase C alpha (PKCα) disrupted polymerization Using proteomics, found that disruption altered expression cytoskeleton-related proteins These findings provide valuable insights into functional potentially opening new perspectives to address sensorineural loss.

Language: Английский

Citations

0
Usher Syndrome: New Insights into Classification, Genotype–Phenotype Correlation, and Management DOI Open Access
Fabiana D’Esposito, Giuseppe Gagliano, Caterina Gagliano

et al.

Genes, Journal Year: 2025, Volume and Issue: 16(3), P. 332 - 332

Published: March 12, 2025

Background: Usher syndrome (USH), the most common cause of combined deaf-blindness, is a genetically and phenotypically heterogeneous disorder characterized by congenital hearing impairment progressive vision loss due to rod-cone dystrophy. Although original classification in three subtypes (USH I, USH II, III) still valid, recent findings have changed widened perspectives its classification, genotype–phenotype correlations, management strategies: Objective: This study aims provide new insights into syndrome, explore genotype-phenotype review current emerging strategies. Methods: A comprehensive literature has been conducted, incorporating data from clinical studies, genetic databases, patient registries. Results: Recent studies led identification several novel pathogenic variants genes, leading refined subclassifications syndrome. Interactions between different genes being part network this ciliopathy investigated mechanisms unveiled. Significant correlations were found certain genotypes presentation both auditory visual phenotypes. For instance, MYO7A gene (USH1B) generally associated with more severe earlier onset retinal dystrophy, if compared other genes-related forms. Other such as USH1G, traditionally considered causing specific subtype, can display phenotypic heterogeneity some patients. Conclusions: provides better understanding that considers regarding causes features. Precise lead counselling, precise characterization natural history condition, personalized effective approach. progress made research gene-specific therapies appear promising for improving quality life individuals affected

Language: Английский

Citations

0
Lifelong dynamic maintenance of stereocilia bundles in mammalian auditory hair cells DOI
A. Catalina Vélez-Ortega, Gregory I. Frolenkov

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

Published: Jan. 1, 2025

Language: Английский

Citations

0
Genetic Association Analysis of Copy Number Variations for Meat Quality in Beef Cattle DOI Creative Commons

Jiayuan Wu,

Tianyi Wu,

Xueyuan Xie

et al.

Foods, Journal Year: 2023, Volume and Issue: 12(21), P. 3986 - 3986

Published: Oct. 31, 2023

Meat quality is an economically important trait for global food production. Copy number variations (CNVs) have been previously implicated in elucidating the genetic basis of complex traits. In this article, we detected a total 112,198 CNVs and 10,102 CNV regions (CNVRs) based on Bovine HD SNP array. Next, performed CNV-based genome-wide association analysis (GWAS) six meat traits identified 12 significant segments corresponding to eight candidate genes, including PCDH15, CSMD3, etc. Using region-based analysis, further relevant beef cattle. Among these, TRIM77 TRIM64 within CNVR4 BTA29 were as genes backfat thickness (BFT). Notably, 34 kb duplication color (MC) which was supported by read-depth signals, embedded keratin gene family KRT4, KRT78, KRT79. Our findings will help dissect architecture from aspects CNVs, subsequently improve selection process breeding programs.

Language: Английский

Citations

8
Proteins required for stereocilia elongation during mammalian hair cell development ensure precise and steady heights during adult life DOI Creative Commons
Ellen I. Hartig, Matthew Day, Amandine Jarysta

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(40)

Published: Sept. 25, 2024

The hair bundle, or stereocilia is the mechanosensory compartment of cells (HCs) in inner ear. To date, most mechanistic studies have focused on bundle morphogenesis, and it remains unclear how this organelle critical for hearing preserves its precise dimensions during life mammals. GPSM2–GNAI complex occupies distal tip tallest row required their elongation development. Here, we ablate adult mouse HCs after normal completed. We observe a progressive height reduction totaling ~600 nm 12 wk Gpsm2 mutant HCs. measure GPSM2 longevity at tips, generated HaloTag-Gpsm2 strain performed pulse–chase experiments vivo. Estimates using tracking loss immunolabeling following inactivation suggest that relatively long-lived tips with half-life 9 to 10 d. Height coincides dampened auditory brainstem responses evoked by low-frequency stimuli particular. Finally, enrichment (EC) partners MYO15A, WHRN, EPS8, mirroring established codependence Taken together, our results show EC also essential mature ensure stable sensitive detection full range sound frequencies.

Language: Английский

Citations

2