Single-cell transcriptomic profiling of the zebrafish inner ear reveals molecularly distinct hair cell and supporting cell subtypes

eLife, Год журнала: 2023, Номер 12

Опубликована: Янв. 4, 2023

A major cause of human deafness and vestibular dysfunction is permanent loss the mechanosensory hair cells inner ear. In non-mammalian vertebrates such as zebrafish, regeneration missing can occur throughout life. While a comparative approach has potential to reveal basis differential regenerative ability, degree which ears fish mammals share common supporting cell types remains unresolved. Here, we perform single-cell RNA sequencing zebrafish ear at embryonic through adult stages catalog diversity non-sensory cells. We identify putative progenitor population for cells, well distinct in maculae versus cristae. The differ from those described lateral line system, distributed organ most studies have been conducted. maculae, two subtypes that gene expression with mammalian striolar or extrastriolar situ hybridization reveals these occupy spatial domains within three macular organs, utricle, saccule, lagena, consistent reported electrophysiological properties domains. These findings suggest primitive specialization spatially likely arose last ancestor mammals. similarities type composition between validate relevant model understanding ear-specific function regeneration.

Язык: Английский

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The forkhead transcription factor Foxj1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation

PLoS Biology, Год журнала: 2024, Номер 22(1), С. e3002468 - e3002468

Опубликована: Янв. 25, 2024

In vertebrates, olfactory receptors localize on multiple cilia elaborated dendritic knobs of sensory neurons (OSNs). Although dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile biogenesis, expressed OSNs required for epithelium (OE) formation. keeping immotile nature cilia, we observed ciliary motility genes are repressed zebrafish, mouse, human OSNs. Strikingly, also found besides ciliogenesis, Foxj1 controls themselves by regulating cell type–specific gene expression, such as marker protein ( omp ) involved odor-evoked signal transduction. line this, response to bile acids, odors detected OMP-positive OSNs, was significantly diminished foxj1 mutant zebrafish. Taken together, our findings establish canonical Foxj1-mediated ciliogenic program been repurposed biogenesis well development

Язык: Английский

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Reproducibility ofin vivoelectrophysiological measurements in mice

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 9, 2022

Abstract Understanding brain function relies on the collective work of many labs generating reproducible results. However, reproducibility has not been systematically assessed within context electrophysiological recordings during cognitive behaviors. To address this, we formed a multi-lab collaboration using shared, open-source behavioral task and experimental apparatus. Experimenters in ten laboratories repeatedly targeted Neuropixels probes to same location (spanning secondary visual areas, hippocampus, thalamus) mice making decisions; this generated total 121 replicates, unique dataset for evaluating electrophysiology experiments. Despite standardizing both procedures, some outcomes were highly variable. A closer analysis uncovered that variability electrode targeting hindered reproducibility, as did limited statistical power routinely used analyses, such single-neuron tests modulation by parameters. Reproducibility was enhanced histological quality-control criteria. Our observations suggest data from systems neuroscience is vulnerable lack but across-lab standardization, including metrics propose, can serve mitigate this.

Язык: Английский

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Mucosal tumor vaccination delivering endogenous tumor antigens protects against pulmonary breast cancer metastases

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(3), С. e008652 - e008652

Опубликована: Март 1, 2024

Background Generally, early-stage breast cancer has a good prognosis. However, if it spreads systemically, especially with pulmonary involvement, prospects worsen dramatically. Importantly, tumor-infiltrating T cells contribute to tumor control, particularly intratumoral tissue-resident memory phenotype are associated an improved clinical outcome. Methods Here, we use adenoviral vector vaccine encoding endogenous tumor-associated antigens adjuvanted interleukin-1β induce tumor-specific (TRM) in the lung for prevention and treatment of metastases murine 4T1 model. Results The mucosal delivery was highly efficient establishing TRM lung. Concomitantly, single vaccination reduced growth survival prophylactic treatment. Vaccine-induced contributed these protective effects. In therapeutic setting, induced pronounced cell infiltration into but resulted only minor restriction disease progression. combination stereotactic radiotherapy, increased time rate tumor-bearing mice. Conclusion summary, our study demonstrates that is promising strategy harness power antitumor its potential state-of-the-art treatments.

Язык: Английский

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Vestibular physiology and function in zebrafish

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Апрель 18, 2023

The vestibular system of the inner ear provides information about head motion and spatial orientation relative to gravity ensure gaze stability, balance, postural control. Zebrafish, like humans, have five sensory patches per that serve as peripheral organs, with addition lagena macula neglecta. zebrafish can be easily studied due its accessible location, transparent tissue larval fish, early development behaviors. Thus, are an excellent model for studying development, physiology, function system. Recent work has made great strides elucidate neural circuitry in tracing transmission from receptors periphery central computational circuits driving reflexes. Here we highlight recent illuminates functional organization epithelia, innervating first-order afferent neurons, second-order neuronal targets hindbrain. Using a combination genetic, anatomical, electrophysiological, optical techniques, these studies probed roles signals fish gaze, postural, swimming We discuss remaining questions tractable model.

Язык: Английский

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Future Pharmacotherapy for Sensorineural Hearing Loss by Protection and Regeneration of Auditory Hair Cells

Pharmaceutics, Год журнала: 2023, Номер 15(3), С. 777 - 777

Опубликована: Фев. 26, 2023

Sensorineural hearing loss has been a global burden of diseases for decades. However, according to recent progress in experimental studies on hair cell regeneration and protection, clinical trials pharmacotherapy sensorineural have rapidly progressed. In this review, we focus protection outline mechanisms based associated studies. Outcomes provided valuable data regarding the safety tolerability intra-cochlear intra-tympanic applications as drug delivery methods. Recent findings molecular suggested realization regenerative medicine near future.

Язык: Английский

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Improved synapsis dynamics accompany meiotic stability in Arabidopsis arenosa autotetraploids

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Abstract During meiosis, the correct pairing, synapsis, and recombination of homologous chromosome pairs is critical for fertility sexual eukaryotes. These processes are challenged in polyploids, which possess additional copies each chromosome. Polyploidy thus provides a unique context to study how evolution can modify meiotic programs response challenges. We previously observed that Arabidopsis arenosa newly formed (neo-)polyploids, synapsis defects precede chromosomes associating aberrant multivalent univalent configurations. Here we dynamics genotypes with varying levels stability ask whether efficient synaptic progression key component evolving stable tetraploid meiosis. develop method quantify using foci pro-crossover factor HEI10 as reference. initially appears at many small loci before accumulating only crossover sites. In diploids, this transition begins while there still significant asynapsis, quickly declines accumulation fewer progresses. neo-tetraploids, suboptimal elongation initiation sites, perhaps defective precedes stalling onset accumulation. established tetraploids, when asynapsis minimal, suggesting an enhanced HEI10/synapsis co-dynamic (even compared diploids). Hybrids generated by crossing neo- tetraploids exhibit intermediate phenotypes. find extent correlates positively numbers, well higher frequency multivalents univalent, disturb segregation. Our work supports hypothesis improving efficiency important polyploid stability. Significance Statement pair subsequently form synaptonemal complex, maturation DNA events. How formation coordinated where multiple sets complicate pair-wise interactions, remains unclear. Leveraging ‘developmental clock,’ quantified new . Synapsis severely compromised ones it more even than diploids. Notably, correlated excess crossovers, compromises connecting connect homologs multivalents. findings highlight polyploids.

Язык: Английский

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Complexes of vertebrate TMC1/2 and CIB2/3 proteins form hair-cell mechanotransduction cation channels

eLife, Год журнала: 2025, Номер 12

Опубликована: Янв. 8, 2025

Calcium and integrin-binding protein 2 (CIB2) CIB3 bind to transmembrane channel-like 1 (TMC1) TMC2, the pore-forming subunits of inner-ear mechano-electrical transduction (MET) apparatus. These interactions have been proposed be functionally relevant across mechanosensory organs vertebrate species. Here, we show that both CIB2 can form heteromeric complexes with TMC1 TMC2 are integral for MET function in mouse cochlea vestibular end as well zebrafish inner ear lateral line. Our AlphaFold models suggest CIB proteins simultaneously interact at least two cytoplasmic domains validated using nuclear magnetic resonance spectroscopy fragments interacting CIB3. Molecular dynamics simulations TMC1/2 CIB2/3 predict TMCs structurally stabilized by cation channels. Overall, our work demonstrates intact hair-cell epithelia.

Язык: Английский

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Coordination of distinct sources of excitatory inputs enhances motion selectivity in the mouse visual thalamus

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

Multiple sources innervate the visual thalamus to influence image-forming vision prior cortex, yet it remains unclear how non-retinal and retinal input coordinate shape thalamic selectivity. Using dual-color two-photon calcium imaging in of awake mice, we observed similar coarse-scale retinotopic organization between axons superior colliculus neurons ganglion cells, both providing strong converging excitatory neurons. At a fine scale ∼10 µm, collicular boutons often shared feature preferences with nearby boutons. Inhibiting significantly suppressed responses specifically reduced motion selectivity preferring nasal-to-temporal motion. The reduction could be result silencing sharply tuned direction-selective colliculogeniculate input. These findings suggest that is not merely relay but selectively integrates inputs from multiple regions build stimulus information transmitted cortex. Chronic reveals diverse tuning axonal boutons.Nearby share at µm scaleSilencing suppresses majority neurons.Silencing reduces

Язык: Английский

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Using Zebrafish to Study the Mechanisms That Underlie Down Syndrome

Опубликована: Янв. 1, 2025

Язык: Английский

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