Abstract
The generation of sensory neurons and hair cells of the inner ear is under tight control. Different members of the Hairy and Enhancer of Split genes (HES) are expressed in the inner ear, their full array of functions still not being disclosed. We have previously shown that zebrafish her9 acts as a patterning gene to restrict otic neurogenesis to an anterior domain. Here, we disclose the role of another her gene, her4, a zebrafish ortholog of Hes5 that is expressed in the neurogenic and sensory domains of the inner ear. The expression of her4 is highly dynamic and spatiotemporally regulated. We demonstrate by loss of function experiments that in the neurogenic domain her4 expression is under the regulation of neurogenin1 (neurog1) and the Notch pathway. Moreover, her4 participates in lateral inhibition during otic neurogenesis since her4 knockdown results in overproduction of the number of neurog1 and deltaB-positive otic neurons. In contrast, during sensorigenesis her4 is initially Notch-independent and induced by atoh1b in a broad prosensory domain. At later stages her4 expression becomes Notch-dependent in the future sensory domains but loss of her4 does not result in hair cell overproduction, suggesting that there other her genes can compensate its function.
Highlights
Distinct proneural genes from the atonal basic helix-loop-helix superfamily control cell fate specification in the inner ear
We have previously demonstrated a role for her9 during otic patterning in restricting neurogenesis to the anterior domain, downstream of retinoic acid (RA) signalling [30] and here concentrated on her4 gene
We have generated a precise map of the expression of her4 at early stages of neuro- and sensorigenesis together with the expression of atoh1b, atoh1a and neurog1. her4 expression is first observed at 12 hpf throughout a broad band of cells just adjacent to the hindbrain
Summary
Distinct proneural genes from the atonal basic helix-loop-helix (bHLH) superfamily control cell fate specification in the inner ear. Drosophila atonal gene was first identified in 1993 [1], its mutation resulting in absence of PNS chordotonal organs and photoreceptors [2]. In vertebrate auditory system one of the atonal orthologs, atoh, is initially expressed in the sensory epithelium to later restrict in nascent hair cells [3]. Either the loss or overexpression of atoh results in complete absence or ectopic differentiation of hair cells [4,5,6]. Two atoh genes are found in the inner ear, which act in two distinct phases of sensory development [7]. Atoh1b appears in a broad prosensory territory to subsequently get restricted to smaller sensory domains. The Notch pathway regulates the production of hair cells and supporting cells via lateral inhibition [8,9,10]
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