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MYO7a is required for the functional integrity of the mechanoelectrical transduction complex in the outer hair cells of the adult cochlea.

ABSTRACT: Myosin-VIIA (MYO7A) in an unconventional myosin responsible for syndromic (Usher 1B) or non-syndromic recessive deafness in humans when mutated. In the cochlea, MYO7A is expressed in the stereocilia of both inner and outer hair cells, where it is believed to act as the motor protein tensioning the mechanoelectrical transducer (MET) channel. Whether this tensioning role is a common feature among both types of cochlear hair cells is unknown. Here we show that MYO7A has a distinct role in adult outer hair cells (OHCs), being crucial for the structural integrity of the MET complex. Postnatal deletion of MYO7A did not affect the staircase structure of the hair bundles but caused a progressive reduction of the size of the MET current without affecting the resting open probability and calcium sensitivity of the MET channel. The hair bundle of OHCs deficient in MYO7A also showed reduced bundle stiffness and was highly susceptible to noise exposure. RNA-sequencing identified the down-regulation of several stereociliary proteins in the Myo7a-deficient cochlea. This study reveals that IHCs and OHCs use different mechanisms to maintain the MET channel in its most sensitive resting open position, and confirms that in OHCs, this mechanism is MYO7A independent.

ORGANISM(S): Mus musculus

PROVIDER: GSE246143 | GEO | 2024/12/23

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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MYO7a is required for the functional integrity of the mechanoelectrical transduction complex in the outer hair cells of the adult cochlea.

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