Development and transdifferentiation into inner hair cells require Tbx2
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ABSTRACT:
PROVIDER: PRJNA819466 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18472400_1.fastq.gz | Fastqsanger.gz | |||
| SRR18472400_2.fastq.gz | Fastqsanger.gz | |||
| SRR18472500_1.fastq.gz | Fastqsanger.gz | |||
| SRR18472500_2.fastq.gz | Fastqsanger.gz | |||
| SRR18472401_1.fastq.gz | Fastqsanger.gz |
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Project description:Atoh1 is essential for the development of both outer hair cells (OHCs) and inner hair cells (IHCs) in the mammalian cochlea. Whereas Ikzf2 is necessary for OHC development, the key gene required for IHC development remains unknown. We found that deletion of Tbx2 in neonatal IHCs led to their transdifferentiation into OHCs by repressing 26.7% of IHC genes and inducing 56.3% of OHC genes, including Ikzf2. More importantly, persistent expression of Tbx2 coupled with transient Atoh1 expression effectively reprogramed non-sensory supporting cells into new IHCs expressing the functional IHC marker vGlut3. The differentiation status of these new IHCs was considerably more advanced than that previously reported. Thus, Tbx2 is essential for IHC development, and co-upregulation of Tbx2 with Atoh1 in supporting cells represents a new approach for treating deafness related to IHC degeneration.
2022-08-09 | GSE199369 | GEO
Project description:The mouse auditory organ cochlea contains two types of sound receptors: inner hair cells (IHCs) and outer hair cells (OHCs). Tbx2 is expressed in IHCs but repressed in OHCs, and neonatal OHCs that misexpress Tbx2 transdifferentiate into IHC-like cells. However, the extent of this switch from OHCs to IHC-like cells and the underlying molecular mechanism remain poorly understood. Furthermore, whether Tbx2 can transform fully mature adult OHCs into IHC-like cells is unknown. Here, our single-cell transcriptomic analysis revealed that in neonatal OHCs misexpressing Tbx2, 85.6% of IHC genes, including Slc17a8, are upregulated, but only 38.6% of OHC genes, including Ikzf2 and Slc26a5, are downregulated. This suggests that Tbx2 cannot fully reprogram neonatal OHCs into IHCs. Moreover, Tbx2 also failed to completely reprogram cochlear progenitors into IHCs. Lastly, restoring Ikzf2 expression alleviated the abnormalities detected in Tbx2+ OHCs, which supports the notion that Ikzf2 repression by Tbx2 contributes to the transdifferentiation of OHCs into IHC-like cells. Our study evaluates the effects of ectopic Tbx2 expression on OHC lineage development at distinct stages of either male or female mice and provides molecular insights into how Tbx2 disrupts the gene-expression profile of OHCs. This research also lays the groundwork for future studies on OHC regeneration.Significance Statement Elucidation of the molecular and genetic mechanisms governing the determination and stability of cochlear inner hair cells (IHCs) and outer hair cells (OHCs) should provide valuable insights into the regeneration of damaged IHCs and OHCs. Here, we conditionally overexpress Tbx2 in vivo in cochlear sensory progenitors, neonatal OHCs, or adult OHCs. Our results show that Tbx2 overexpression alone can partially destabilize the OHC fate but cannot fully convert OHCs into IHCs. Specifically, we demonstrate that Ikzf2 repression due to Tbx2 overexpression is one of the key pathways disrupting the OHC fate.
2024-05-21 | GSE233559 | GEO
Project description:Atoh1 is essential for the development of both outer hair cells (OHCs) and inner hair cells (IHCs) in the mammalian cochlea. Whereas Ikzf2 is necessary for OHC development, the key gene required for IHC development remains unknown. We found that deletion of Tbx2 in neonatal IHCs led to their transdifferentiation into OHCs by repressing 26.7% of IHC genes and inducing 56.3% of OHC genes, including Ikzf2. More importantly, persistent expression of Tbx2 coupled with transient Atoh1 expression effectively reprogrammed non-sensory supporting cells into new IHCs expressing the functional IHC marker vGlut3. The differentiation status of these new IHCs was considerably more advanced than that previously reported. Thus, Tbx2 is essential for IHC development and co-upregulation of Tbx2 with Atoh1 in supporting cells represents a new approach for treating deafness related to IHC degeneration.
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Project description:Cochlear inner hair cells (IHCs) and outer hair cells (OHCs) require different transcription factors for their cell fate stabilization and survival, suggesting separate mechanisms are involved. Here, we found that the transcription factor Casz1 was crucial for early IHC fate consolidation and for OHC survival during mouse development. Loss of Casz1 resulted in transdifferentiation of IHCs into OHCs, without affecting OHC production. However, long-term OHC survival was compromised in Casz1 mutant mice. In addition, the transcription factor Gata3 was downregulated in Casz1-deleted IHCs and overexpressing Gata3 partially rescued IHC properties, OHC numbers, and hearing in Casz1-deleted mice. Thus, Casz1 plays critical roles in early IHC fate stabilization and OHC survival and could potentially provide a lead for therapies aimed at regenerating both IHCs and OHCs.
2025-02-01 | GSE249055 | GEO
Project description:Cochlear inner hair cells (IHCs) and outer hair cells (OHCs) require different transcription factors for their cell fate stabilization and survival, suggesting separate mechanisms are involved. Here, we found that the transcription factor Casz1 was crucial for early IHC fate consolidation and for OHC survival during mouse development. Loss of Casz1 resulted in transdifferentiation of IHCs into OHCs, without affecting OHC production. However, long-term OHC survival was compromised in Casz1 mutant mice. In addition, the transcription factor Gata3 was downregulated in Casz1-deleted IHCs and overexpressing Gata3 partially rescued IHC properties, OHC numbers, and hearing in Casz1-deleted mice. Thus, Casz1 plays critical roles in early IHC fate stabilization and OHC survival and could potentially provide a lead for therapies aimed at regenerating both IHCs and OHCs.
2025-02-01 | GSE279618 | GEO
Project description:The morphogenesis of the otic vesicle (OV) to form inner ear organs serves as an excellent model system to understand cell fate acquisition on a single cell level. Tbx2 and Tbx3 (Tbx2/3) encode closely related T-box transcription factors that are expressed widely in the mammalian otic vesicle (OV). Inactivation of both genes in the Pax2-Cre lineage (Tbx2/3cKO) results in failed morphogenesis of the OV into inner ear organs. To understand the basis of these defects, single cell RNA-sequencing (scRNA-seq) was performed on the OV lineage using Pax2-Cre, in controls versus Tbx2/3cKO embryos, at stage E10.5. We identified a multipotent population termed otic progenitors that are localized to the anterior ventrolateral region of the OV in controls and are marked by expression of Fgf18, Sox3, and Cxcl12. The otic progenitor population was increased three-fold in Tbx2/3cKO embryos, concomitant with dysregulation of genes in these cells as well as reduced progression to more differentiated states of prosensory and nonsensory cells. An ectopic neural population of cells was detected in the posterior OV of Tbx2/3cKO embryos due to increased expression of Neurog1 and NeuroD1 but with reduced maturation. As all three cell fates were affected in Tbx2/3cKO embryos, we suggest that Tbx2/3 promotes progression of multipotent otic progenitors to more differentiated cell types in the OV.
2022-12-12 | GSE185172 | GEO
Project description:Revisiting the potency of Tbx2 expression in transforming outer hair cells into inner hair cells at multiple ages in vivo
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Project description:Cochlear inner hair cells (IHCs) are primary sound receptors, and thus in efforts to develop treatments for hearing impairment. IHC regeneration in vivo has been widely attempted, although not yet in the IHC-damaged cochlea. Moreover, the extent to which new IHCs resemble wild-type IHCs remains unclear, as does whether new IHCs can yield hearing improvement. Here, we developed an in vivo mouse model wherein wild-type IHCs were pre-damaged and nonsensory supporting cells were transformed into IHCs by ectopically expressing Atoh1 transiently and Tbx2 permanently. Notably, the new IHCs expressed the functional marker vGlut3 and presented similar transcriptomic and electrophysiological properties as wild-type IHCs. Furthermore, the formation efficiency and maturity of new IHCs were higher than those previously reported, although marked hearing improvement was not achieved, at least partly due to defective mechanoelectrical transduction (MET) in new IHCs. Thus, we successfully regenerated new IHCs resembling wild-type IHCs in multiple aspects in the damaged cochlea. Our findings suggest that the defective MET is a critical barrier preventing the restoration of hearing capacity and should thus facilitate future IHC regeneration studies.
2023-11-05 | GSE188259 | GEO
Project description:To further understand the biological properties of hair cells of the mammalian cochlea, we examined the transcriptome of adult inner and outer hair cells. Morphologically distinct inner and outer hair cells were isolated from the organ of Corti from adult CBA/J mice. One thousand inner and outer hair cells were separately collected for each biological replicate, using the suction pipette technique. RNA sequencing of two biological replicates of IHCs and three biological replicates of OHCs, each with two technical repeats, was performed. The resulting sequenced reads were mapped. Comparisons between inner and outer hair cells allow identification of enriched genes, as well as differentially expressed genes that result in cellular specialization. Our dataset provides an extensive resource for understanding the molecular mechanisms underlying morphology, function, and pathology of adult mouse inner and outer hair cells.
2018-08-02 | GSE111348 | GEO
Project description:Latent transdifferentiation potential exists in supporting cells at neonatal stage in the organ of Corti in mouse, but this plasticity is lost rapidly during the first week of postnatal maturation, leading to the failure of sensory hair cell regeneration. To investigate the molecular mechanism underlying the loss of transdifferentiation potential, we compared epigenetic changes in E17.5, P1 and P6 supporting cells. In E17.5 and P1 supporting cells, hair cell gene enhancers are kept in a primed state (H3K4me1+ H3K27ac-) which can be readily activated during transdifferentiation induced by Notch blocking. As supporting cells mature, a substantial amount of hair cell gene enhancers are decommissioned by H3K4me1, leading to the loss of transdifferentiation potential. In contrast, hair cell gene enhancers retain their commissioned epigenetic status in mature utricular supporting cells, sustaining the transidifferentiation potential in utricular supporting cells in mature animals. Our findings reveal the epigenetic mechanisms underlying the failure of sensory hair cell regeneration in mammalian cochlea.
2021-07-09 | GSE150010 | GEO