Functional Features of Trans-Differentiated Hair Cells Mediated by Atoh1 Reveals a Primordial Mechanism

Abstract

Evolution has transformed a simple ear with few vestibular maculae into a complex three-dimensional structure consisting of nine distinct endorgans. It is debatable whether the sensory epithelia underwent progressive segregation or emerged from distinct sensory patches. To address these uncertainties we examined the morphological and functional phenotype of trans-differentiated rat hair cells to reveal their primitive or endorgan-specific origins. Additionally, it is uncertain how Atoh1-mediated trans-differentiated hair cells trigger the processes that establish their neural ranking from the vestibulocochlear ganglia. We have demonstrated that the morphology and functional expression of ionic currents in trans-differentiated hair cells resemble those of "ancestral" hair cells, even at the lesser epithelia ridge aspects of the cochlea. The structures of stereociliary bundles of trans-differentiated hair cells were in keeping with cells in the vestibule. Functionally, the transient expression of Na⁺ and I(h) currents initiates and promotes evoked spikes. Additionally, Ca²⁺ current was expressed and underwent developmental changes. These events correlate well with the innervation of ectopic hair cells. New "born" hair cells at the abneural aspects of the cochlea are innervated by spiral ganglion neurons, presumably under the tropic influence of chemoattractants. The disappearance of inward currents coincides well with the attenuation of evoked electrical activity, remarkably recapitulating the development of hair cells. Ectopic hair cells underwent stepwise changes in the magnitude and kinetics of transducer currents. We propose that Atoh1 mediates trans-differentiation of morphological and functional "ancestral" hair cells that are likely to undergo diversification in an endorgan-specific manner.