The cochlea phenotypically differs from the vestibule in the Gfi1^GFP/GFP mouse

Developmental Dynamics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Abstract Background Previous studies with Gfi1 ‐mutated lines have shown that is essential for hair cell maturation and survival. Results We analyzed the phenotype of another line GFP/GFP in inner ears neonates at P5‐7 found cochlea phenotypically differed from vestibule mouse. Specifically, there was a marked reduction cells cochlea, which characterized by greater reductions outer but far less (mainly basal turn) cells, whereas vestibular remained unaffected. These results were consistent findings previous studies. Unexpectedly, number cochlear non‐sensory supporting significantly decreased. However, did not demonstrate any abnormalities number. Conclusion exhibits different functions during ear development.

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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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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Hearing Restoration through Hair Cell Regeneration: A Review of Recent Advancements and Current Limitations

Hearing Research, Год журнала: 2025, Номер unknown, С. 109256 - 109256

Опубликована: Март 1, 2025

Язык: Английский

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Regeneration of sensory hair cells in mature mammals

Current topics in developmental biology/Current Topics in Developmental Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining mouse cochlear hair cell survival

eLife, Год журнала: 2024, Номер 12

Опубликована: Март 14, 2024

Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms maintain HC survival is crucial for preventing hearing impairment. Intriguingly, Pou4f3 -/- or Gfi1 HCs form initially but then rapidly degenerate, whereas Rbm24 degenerate considerably later. However, transcriptional cascades involving Pou4f3, Gfi1, and remain undescribed. Here, we demonstrate expression completely repressed in unaltered HCs, further both POU4F3 GFI1 intact HCs. Moreover, by using vivo mouse transgenic reporter assays, identify three enhancers to which binds. Lastly, through genetic testing whether restoration alleviates degeneration show ectopic alone prevent from degenerating. Collectively, our findings provide new insights into how regulated.

Язык: Английский

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Single-cell atlas comparison across vertebrates reveals evolution of auditory cell types and mechanisms for hair cell regeneration

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 28, 2024

The loss of auditory hair cell in mammals including humans results permanent hearing impairment, as they lack the inherent capacity for regeneration. In contrast, lower vertebrates exhibit remarkable regeneration and restoration, however, mechanisms remain unclear. this work, we characterized first single-cell atlas inner ear from high regenerative species Xenopus laevis further performed a comprehensive comparison with mouse model. An exceptionally conserved neuronal type was discovered confirmed across species. Comprehensive characterization revealed that outer cells (OHCs) represent newly evolved subtype, existing exclusively mammals. Importantly, our analyses an orchestrated gene expression program highly Xenopus, by upregulation genes associated regeneration, coupled downregulation proliferation inhibitory genes. These findings unveil natural feature provide molecular evolutionary evidences regulatory differential capacities vertebrates. This work offers novel insights amphibian into developing strategies to solve challenges repair humans.

Язык: Английский

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Frameshift variants in TBX2 underlie autosomal-dominant hearing loss with incomplete penetrance of nystagmus

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 19, 2024

Abstract Purpose The transcription factor TBX2 plays a critical role in inner hair cells development mice. Yet, the link between malfunction and human hearing-related disorders remains unexplored. Methods Linkage analysis combined with whole genome sequencing was applied to identify causative gene two autosomal dominant Chinese families characterized by late-onset progressive sensorineural hearing loss incomplete penetrance of horizontal oscillatory nystagmus. Functional evaluation variants performed through protein expression, localization, transcriptional activity vitro , phenotypic mechanism study knockout mice model vivo . Results Multipoint parametric linkage Family 1 revealed maximum LOD score 3.01 on chromosome 17q23.2. Whole identified distinct variants, c.977delA (p.Asp326Alafs*42) c.987delC (p.Ala330Argfs*38) each family, co-segregating loss. These resulted premature termination generation new peptide segment, reducing activity. Further, heterozygous Tbx2 exhibited loss, along ectopic expression Prestin IHCs gradual decrease from P7 P42. Conclusion Our findings indicate that frameshift are genetic cause mouse mirrored phenotype, further validating TBX2’s auditory function. insights enhance our understanding system, providing valuable information for molecular diagnostics counseling related disorders.

Язык: Английский

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Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining mouse cochlear hair cell survival

eLife, Год журнала: 2023, Номер 12

Опубликована: Июль 25, 2023

Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms maintain HC survival is crucial for preventing hearing impairment. Intriguingly, Pou4f3-/- or Gfi1-/- HCs form initially but then rapidly degenerate, whereas Rbm24-/- degenerate considerably later. However, transcriptional cascades involving Pou4f3, Gfi1, and Rbm24 remain undescribed. Here, we demonstrate expression completely repressed in unaltered HCs, further both POU4F3 GFI1 intact HCs. Moreover, by using vivo mouse transgenic reporter assays, identify three enhancers to which binds. Lastly, through genetic testing whether restoration alleviates degeneration show ectopic alone prevent from degenerating. Collectively, our findings provide new insights into how regulated.

Язык: Английский

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Deciphering the genetic interactions between Pou4f3, Gfi1, and Rbm24 in maintaining cochlear hair cell survival

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

Опубликована: Июнь 22, 2023

ABSTRACT Mammals harbor a limited number of sound-receptor hair cells (HCs) that cannot be regenerated after damage. Thus, investigating the underlying molecular mechanisms maintain HC survival is crucial for preventing hearing impairment. Intriguingly, Pou4f3 -/- or Gfi1 HCs form initially but then rapidly degenerate, whereas Rbm24 degenerate considerably later. However, transcriptional cascades involving Pou4f3, Gfi1, and remains undescribed. Here, we demonstrate expression completely repressed in unaltered HCs, further both POU4F3 GFI1 intact HCs. Moreover, by using vivo mouse transgenic reporter assays, identify three enhancers to which binds. Lastly, through genetic testing whether restoration alleviates degeneration show ectopic alone prevent from degenerating. Collectively, our findings provide new insights into how regulated.

Язык: Английский

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