Harmony in the Molecular Orchestra of Hearing: Developmental Mechanisms from the Ear to the Brain

Annual Review of Neuroscience, Год журнала: 2024, Номер 47(1), С. 1 - 20

Опубликована: Фев. 16, 2024

Auditory processing in mammals begins the peripheral inner ear and extends to auditory cortex. Sound is transduced from mechanical stimuli into electrochemical signals of hair cells, which relay information via primary neurons cochlear nuclei. Information subsequently processed superior olivary complex, lateral lemniscus, inferior colliculus projects cortex medial geniculate body thalamus. Recent advances have provided valuable insights development functioning structures, complementing our understanding physiological mechanisms underlying processing. This comprehensive review explores genetic required for system cochlea We highlight transcription factors other genes with key recurring interacting roles guiding organization. Understanding these gene regulatory networks holds promise developing novel therapeutic strategies hearing disorders, benefiting millions globally.

Язык: Английский

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Casz1 is required for both inner hair cell fate stabilization and outer hair cell survival

Science, Год журнала: 2025, Номер unknown

Опубликована: Янв. 30, 2025

Cochlear inner hair cells (IHCs) and outer (OHCs) require different transcription factors for their cell fate stabilization survival, suggesting separate mechanisms are involved. Here, we found that the factor Casz1 was crucial early IHC consolidation OHC survival during mouse development. Loss of resulted in transdifferentiation IHCs into OHCs, without affecting production. However, long-term compromised mutant mice. In addition, Gata3 down-regulated -deleted overexpressing partially rescued properties, numbers, hearing Thus, plays critical roles could potentially provide a lead therapies aimed at regenerating both OHCs.

Язык: Английский

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Identification of multiple transcription factor genes potentially involved in the development of electrosensory versus mechanosensory lateral line organs

Frontiers in Cell and Developmental Biology, Год журнала: 2024, Номер 12

Опубликована: Март 18, 2024

In electroreceptive jawed vertebrates, embryonic lateral line placodes give rise to electrosensory ampullary organs as well mechanosensory neuromasts. Previous reports of shared gene expression suggest that conserved mechanisms underlie electroreceptor and hair cell development electroreceptors evolved a transcriptionally related “sister type” cells. We previously identified only one transcription factor gene, Neurod4 , organ-restricted in the developing system chondrostean ray-finned fish, Mississippi paddlefish ( Polyodon spathula ). The other 16 genes we validated were expressed both Here, used our published organ-enriched gene-set (arising from differential bulk RNA-seq late-larval paddlefish), together with candidate approach, identify 25 more experimentally tractable chondrostean, sterlet Acipenser ruthenus small sturgeon), and/or paddlefish. Thirteen are neuromasts, consistent conservation molecular mechanisms. Seven electrosensory-restricted on head Irx5 Irx3 Insm1 Sp5 Satb2 Mafa Rorc ), five first-reported mechanosensory-restricted Foxg1 Sox8 Isl1 Hmx2 Rorb However, reported, is neuromasts catshark Scyliorhinus canicula suggesting existence lineage-specific differences between cartilaginous fishes. Overall, results support hypothesis develop via largely transcriptional mechanisms, multiple factors potentially involved formation versus organs.

Язык: Английский

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In situ regeneration of inner hair cells in the damaged cochlea by temporally regulated co-expression of Atoh1 and Tbx2

Development, Год журнала: 2023, Номер 150(24)

Опубликована: Дек. 11, 2023

Cochlear inner hair cells (IHCs) are primary sound receptors, and therefore a target for developing treatments hearing impairment. IHC regeneration in vivo has been widely attempted, although not yet the IHC-damaged cochlea. Moreover, extent to which new IHCs resemble wild-type remains unclear, as is ability of improve hearing. Here, we have developed an mouse model wherein were pre-damaged nonsensory supporting transformed into by ectopically expressing Atoh1 transiently Tbx2 permanently. Notably, expressed functional marker vGlut3 presented similar transcriptomic electrophysiological properties IHCs. Furthermore, formation efficiency maturity higher than those previously reported, marked improvement was achieved, at least partly due defective mechanoelectrical transduction (MET) Thus, successfully regenerated resembling many respects damaged Our findings suggest that MET critical barrier prevents restoration capacity should thus facilitate future studies.

Язык: Английский

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Revisiting the potency of Tbx2 expression in transforming outer hair cells into inner hair cells at multiple ages in vivo

Journal of Neuroscience, Год журнала: 2024, Номер 44(23), С. e1751232024 - e1751232024

Опубликована: Апрель 30, 2024

The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer (OHCs). Tbx2 is expressed in IHCs but repressed OHCs, neonatal OHCs that misexpress transdifferentiate into IHC-like cells. However, the extent this switch from to underlying molecular mechanism remain poorly understood. Furthermore, whether can transform fully mature adult unknown. Here, our single-cell transcriptomic analysis revealed misexpressing Tbx2, 85.6% IHC genes, including Slc17a8 , are upregulated, only 38.6% OHC Ikzf2 Slc26a5 downregulated. This suggests cannot reprogram IHCs. Moreover, also failed completely cochlear progenitors Lastly, restoring expression alleviated abnormalities detected Tbx2+ which supports notion repression by contributes transdifferentiation Our study evaluates effects ectopic on lineage development at distinct stages either male or female mice provides insights how disrupts gene profile OHCs. research lays groundwork for future studies regeneration.

Язык: Английский

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Metabolic Profiling of Cochlear Organoids Identifies α‐Ketoglutarate and NAD⁺ as Limiting Factors for Hair Cell Reprogramming

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Июль 11, 2024

Cochlear hair cells are the sensory responsible for transduction of acoustic signals. In mammals, damaged do not regenerate, resulting in permanent hearing loss. Reprogramming surrounding supporting to functional represent a novel strategy restoration. However, cellular processes governing efficient and cell reprogramming completely understood. Employing mouse cochlear organoid system, detailed metabolomic characterizations expanding differentiating organoids performed. It is found that differentiation associated with increased mitochondrial electron transport chain (ETC) activity reactive oxidative species generation. Transcriptome metabolome analyses indicate reduced expression oxidoreductases tricyclic acid (TCA) cycle metabolites. The metabolic decoupling between ETC TCA limits availability key cofactors, α-ketoglutarate (α-KG) nicotinamide adenine dinucleotide (NAD

Язык: Английский

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Comparative biology of the amniote vestibular utricle

Hearing Research, Год журнала: 2024, Номер 448, С. 109035 - 109035

Опубликована: Май 19, 2024

The sensory epithelia of the auditory and vestibular systems vertebrates have shared developmental evolutionary histories. However, while show great variation across vertebrates, appear seemingly more conserved. An exploration current knowledge comparative biology amniote utricle, a epithelium that senses linear acceleration, shows interesting instances variability between birds mammals. distribution hair cell types, position line bundle polarity reversal properties supporting cells marked differences, likely impacting function regeneration potential.

Язык: Английский

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Irx3/5 Null Deletion in Mice Blocks Cochlea‐Saccule Segregation and Disrupts the Auditory Tonotopic Map

The Journal of Comparative Neurology, Год журнала: 2024, Номер 532(12)

Опубликована: Дек. 1, 2024

A gene cadre orchestrates the normal development of sensory and non-sensory cells in inner ear, segregating cochlea with a distinct tonotopic sound frequency map, similar brain projection, five vestibular end-organs. However, role genes driving ear is largely unknown. Here, we show double deletion Iroquois homeobox 3 5 transcription factors (Irx3/5 DKO) leads to fusion saccule cochlear base. The overlying otoconia tectorial membranes are absent Irx3/5 DKO primary auditory neurons project fibers both hair cells. central neuronal projections from apex-base contour not fully segregated into dorsal ventral innervation nucleus, obliterating characteristic map. Additionally, reveals pronounced cochlear-apex-vestibular "vestibular-cochlear" nerve (VCN) bilateral connection that less noticeable wild-type control mice. Moreover, incomplete segregation apex base expands connect nuclei. results suggest mammalian derived lagena reminiscent sarcopterygians. Thus, Irx3 potential evolutionary branch-point necessary for balance-sound segregation, which fused saccule-cochlea organization.

Язык: Английский

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Revisiting the potency of Tbx2 expression in transforming outer hair cells into inner hair cells at multiple agesin vivo

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Сен. 17, 2023

Abstract The cochlea, the auditory organ, contains two types of sound receptors: inner hair cells (IHCs) and outer (OHCs). Tbx2 is expressed in IHCs but repressed OHCs. neonatal OHCs with misexpression transdifferentiate into IHC-like cells. However, extent switch from to underlying molecular mechanism remain poorly understood. Furthermore, it unknown whether can transform fully mature adult In this study, we employ single-cell transcriptomic analysis, revealing that 85.6% IHC genes, including Slc17a8 , are upregulated, whereas only 38.6% OHC Ikzf2 Slc26a5 downregulated misexpression. Thus, our findings suggest cannot reprogram IHCs, contrary previous assumptions. Consistently, also fails cochlear progenitors IHCs. Finally, restoration alleviates abnormalities present Tbx2+ OHCs, supporting notion repression by contributes transdifferentiation Overall, study reevaluates effects ectopic expression on lineage development at different stages provides insights how disrupts gene profiles This research lays groundwork for future studies regeneration. Significance Statement Understanding genetic mechanisms govern determination stability (OHCs) would provide valuable regenerating damaged manuscript, conduct vivo conditional overexpression sensory progenitors, respectively. Our challenge assumptions alone partially destabilize fates convert Specifically, demonstrate due one key pathways disrupting fate.

Язык: Английский

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Editorial Overview: Molecular neuroscience

Current Opinion in Neurobiology, Год журнала: 2024, Номер 86, С. 102873 - 102873

Опубликована: Апрель 2, 2024

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