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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE215951 | GEO | 2023/01/01

REPOSITORIES: GEO

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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.

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

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