Abstract
Atonal homolog1 (Atoh1) is a bHLH transcription factor essential for inner ear hair cell differentiation. Targeted expression of Atoh1 at various stages in development can result in hair cell differentiation in the ear. However, the level and duration of Atoh1 expression required for proper hair cell differentiation and maintenance remain unknown. We generated an Atoh1 conditional knockout (CKO) mouse line using Tg(Atoh1-cre), in which the cre expression is driven by an Atoh1 enhancer element that is regulated by Atoh1 protein to “self-terminate” its expression. The mutant mice show transient, limited expression of Atoh1 in all hair cells in the ear. In the organ of Corti, reduction and delayed deletion of Atoh1 result in progressive loss of almost all the inner hair cells and the majority of the outer hair cells within three weeks after birth. The remaining cells express hair cell marker Myo7a and attract nerve fibers, but do not differentiate normal stereocilia bundles. Some Myo7a-positive cells persist in the cochlea into adult stages in the position of outer hair cells, flanked by a single row of pillar cells and two to three rows of disorganized Deiters cells. Gene expression analyses of Atoh1, Barhl1 and Pou4f3, genes required for survival and maturation of hair cells, reveal earlier and higher expression levels in the inner compared to the outer hair cells. Our data show that Atoh1 is crucial for hair cell mechanotransduction development, viability, and maintenance and also suggest that Atoh1 expression level and duration may play a role in inner vs. outer hair cell development. These genetically engineered Atoh1 CKO mice provide a novel model for establishing critical conditions needed to regenerate viable and functional hair cells with Atoh1 therapy.
Highlights
Sensorineural hearing loss is one of the most common sensory disorders and mostly results from loss of cochlea hair cells in the inner ear
Was used to drive cre expression [14]. The activation of this enhancer is dependent on the Atonal homolog1 (Atoh1) protein, which binds to the enhancer and upregulates both endogenous Atoh1 expression and cre expression from the transgene and can ‘self-terminate’ its expression through Cre mediated recombination (Fig. 1a)
We present here the first genetically engineered animal model that directly affects both level and duration of Atoh1 expression in the ear
Summary
Sensorineural hearing loss is one of the most common sensory disorders and mostly results from loss of cochlea hair cells in the inner ear. The most frequently manipulated gene in these studies is Atoh, a proneural basic helix-loop-helix (bHLH) transcription factor that is essential for inner ear hair cell differentiation [8]. The level and duration of Atoh expression required for normal hair cell development and successful regeneration of viable hair cells has not been determined. It remains unclear if some differentiation might be possible with limited or transient expression of Atoh
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