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Development and transdifferentiation into inner hair cells require Tbx2

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE199369 | GEO | 2022/08/09

REPOSITORIES: GEO

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

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

Transcriptomes of the Cochlear Inner and Outer Hair Cells

Project description:The transcriptome is the complete set of all RNA transcripts produced by the genome in a cell and reflects the genes that are being actively expressed. Transcriptome analysis is essential for understanding the genetic mechanism controlling the phenotype of a cell. Using DNA microarray technique we examined transcriptomes of 2,000 individually collected inner (IHCs) and outer hair cells (OHCs), two types of auditory sensory cells critical for hearing. Among approximately 16,645 and 17,711 transcripts considered to be expressed, 1,296 and 256 genes showed significant differential expression in IHCs and OHCs, respectively. The top ten differentially expressed genes include Slc17a8, Dnajc5b, Slc1a3, Atp2a3, Osbpl6, Slc7a14, Bcl2, Bin1, Prkd1, Map4k4 in IHCs, and Slc26a5, C1ql1, Strc, Dnm3, Plbd1, Lbh, Olfm1, Plce1, Tectb, Ankrd22 in OHCs. Many unknown sequences and non-coding RNAs were also expressed in hair cells. The differentially expressed genes underlie the genetic mechanism for unique functions of IHCs and OHCs. The total RNA was extracted from the collected pools of single outer hair cell (OHC) and inner hair cell (IHC). Their whole-genome transcriptome expression was detected using GeneChip microarray analysis. The analysis and comparison between OHC and IHC allow us to determine what genes are expressed and what genes are uniquely or differential expressed in each population.

2014-08-12 | E-GEOD-56866 | biostudies-arrayexpress

Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells

Project description:Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represented a barrier to restoring auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single cell RNA sequencing reveals the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.

2021-09-03 | GSE161156 | GEO

Transcriptomes of the Cochlear Inner and Outer Hair Cells

2014-08-12 | GSE56866 | GEO

Transcriptomic and epigenetic regulation of hair cell regeneration in the mouse utricle and its potentiation by Atoh1

Project description:The mammalian cochlea loses its ability to regenerate new hair cells prior to the onset of hearing. In contrast, the adult vestibular system can produce new hair cells in response to damage, or by reprogramming of supporting cells with the hair cell transcription factor Atoh1. We used RNA-seq and ATAC-seq to probe the transcriptional and epigenetic responses of utricle supporting cells to damage and Atoh1 transduction. We show that the improved regenerative response of the utricle correlates with a more accessible chromatin structure in utricle supporting cells compared to their cochlear counterparts. We also provide evidence that Atoh1 transduction of supporting cells is able to promote increased transcriptional accessibility of some hair cell genes. Our study offers a possible explanation for regenerative differences between sensory organs of the inner ear, but shows that additional factors to Atoh1 may be required for optimal reprogramming of hair cell fate.

2019-04-30 | GSE121610 | GEO

Characterization of the transcriptomes of Atoh1-induced hair cells in the mouse cochlea

Project description:Mammalian cochlea hair cells can be regenerated from the adjacent supporting cells in many ways, however, the newly hair cells are immature and without hearing function almost. The expression of Atoh1 is an important maker of the appearance of newly hair cells, many approaches of inner ear hair cells’ regeneration are concerned with the transcription factor Atoh1. However, most new HCs are immature HCs, and they do not have the function of mature HCs and eventually die a few weeks after regeneration. Thus promoting the maturation and survival of new HCs is the primary focus of HC regeneration field. We used RNA-Seq analysis to compare the differences between the transcriptomes of Atoh1 overexpression-induced new HCs and the original HCs, and to define the factors that might help to promote the maturation and survival of new HCs.

2019-04-10 | GSE129533 | GEO

Proteomic analysis reveals the composition of glutamatergic organelles of auditory inner hair cells

Project description:In the ear, inner hair cells (IHCs) employ sophisticated glutamatergic ribbon synapses with afferent neurons to transmit auditory information to the brain. The presynaptic machinery responsible for neurotransmitter release in IHC synapses includes proteins such as the multi-C2-domain protein otoferlin and the vesicular glutamate transporter 3 (VGluT3). Yet, much of this likely unique molecular machinery remains to be deciphered. The scarcity of material has so far hampered biochemical studies which require large amounts of purified sample. We developed a subcellular fractionation workflow combined with immunoisolation of VGluT3-containing membrane vesicles, allowing for the enrichment of IHC trafficking glutamatergic organelles that are likely dominated by synaptic vesicles (SVs) of IHCs. We have characterized their protein composition in mice before and after hearing onset using mass spectrometry and confocal imaging and provide a fully annotated proteome with hitherto unidentified proteins. Despite the prevalence of IHC marker proteins across IHC maturation, the profiles of trafficking proteins differed markedly before and after hearing onset. Our study provides an inventory of the machinery associated with synaptic vesicle-mediated trafficking and presynaptic activity at IHC ribbon synapses and serves as a foundation for future functional studies.

2024-02-09 | PXD046664 | Pride

Spontaneous firing activity in pre-hearing inner hair cells regulates the maturation of the mechanoelectrical transducer apparatus over a critical time-period

Project description:Sensory-independent Ca2+ spiking activity is crucial for the development of mammalian sensory systems. In the cochlea, spontaneous Ca2+ action potentials (APs) are present in the pre-hearing inner hair cells (IHCs), the frequency and pattern of which is modulated by ATP-dependent intercellular Ca2+ waves in the non-sensory cells. It remains unknown whether both these Ca2+-dependent signalling mechanisms in the cochlea are required for the functional maturation of the IHCs. We found that the intrinsic Ca2+ AP activity, but not that triggered by Ca2+ signalling in the non-sensory cells, regulates the maturation and maintenance of the stereociliary hair bundle in IHCs. We used a mouse model in which the potassium channel Kir2.1 is reversibly overexpressed in IHCs in vivo. Kir2.1 overexpression (Kir2.1-OE mice) prevented spontaneous Ca2+ spikes in IHCs, but not their modulation by ATP-induced signalling from non-sensory cells. Without spontaneous Ca2+ APs, mechanoelectrical transduction in IHCs disappeared prior the onset of hearing at P12 due to the progressive loss of stereocilia and their fusion. RNA-sequencing data showed that several pathways, including those involved in morphogenesis, actin-filament based processes, and Rho-GTPase signalling, were upregulated during the second postnatal week. By manipulating the in vivo expression of Kir2.1 channels, we identified the second post-natal week as the “critical point” after which spontaneous Ca2+ APs are required for proper hair bundle maintenance. We showed that the final stage of IHC maturation is finely regulated by their intrinsic electrical activity just before sound-induced sensory driven activity.

2023-01-01 | GSE215951 | GEO

RNA-sequencing of Adult Mouse Inner Hair Cells and Outer Hair Cells of the organ of Corti

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

Analyses of iHC transcriptome profiles

Project description:Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. However, very little is known about the transcriptional regulators involved in HC fate determination and differentiation. In this paper, we show that expression of three HC lineage-specific transcription factors: Gfi1, Pou4f3 and Atoh1, can induce a direct commitment towards HC fate during in vitro embryonic stem cell (ESC) differentiation. Induced HCs (iHCs) express numerous HC-specific genes and exhibit polarized membrane protusions reminiscent of stereociliary bundles. The ability to obtain purified populations of iHCs by virtue of the Myo7:mVenus reporter line (iGPA-Myo7a:mVenus) allowed us to generate highly reproducible gene expression profiles for these cells, at various phases of their development (day 8 and day 12 of cell culture).

2015-06-02 | GSE60352 | GEO

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