Gómez Dorado, M; (2017) Investigation and comparison of the regulation of ATOH1 in the mammalian and avian inner ear. Doctoral thesis , UCL (University College London).

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Abstract

Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor required for the formation of sensory hair cells in the inner ear (Bermingham et al. 1999). Understanding the Atoh1 regulatory network is crucial for the development of new therapies to treat hearing loss. However, to date, little is known about the mechanisms controlling ATOH1 expression. The loss of sensory hair cells can cause deafness and balance disorders. In the mammalian inner ear, the loss of ATOH1 expression in adults has been linked with a limited capacity to regenerate hair cells (Wang et al. 2010). However, in non-mammalian vertebrates, ATOH1 expression re-activates spontaneously after hair cell damage and new hair cells can be formed throughout life (Cafaro et al. 2007) (Daudet et al. 2009). In this thesis, I aimed to identify regulatory elements responsible for ATOH1 expression through a comparative analysis of avian and mammalian ATOH1 gene loci. A bioinformatic approach was used to identify evolutionary conserved non-coding ATOH1 DNA sequences including those that are conserved between avian and mammals and those that are specific to both groups. Putative transcription factor binding sites predicted within these conserved elements were then investigated using EMSA analysis and reporter gene assays. These experiments suggest that the E2F1 transcription factor activates the chick ATOH1 gene and that this activation occurs predominantly via a direct interaction with a regulatory region that is conserved between avian species but absent from mammals. E2F transcription factors control cell cycle progression so the identification of this family as novel regulators of the chick ATOH1 expression links avian ATOH1 re-activation to cell proliferation. If confirmed, this would provide a possible mechanism to explain the different regenerative capabilities of mammalian and non-mammalian sensory cells and therefore contribute to the design of therapies for the regeneration of hair cells after damage.

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