An Atoh1-S193A Phospho-Mutant Allele Causes Hearing Deficits and Motor Impairment

作者：Wei Rose Xie, Hsin‐I Jen, Michelle L. Seymour, Szu-Ying Yeh, Fred A. Pereira, Andrew K. Groves, Tiemo J. Klisch, Huda Y. Zoghbi · 发表于：Journal of Neuroscience · 年份：2017 · DOI：10.1523/jneurosci.0295-17.2017 · 被引用次数：32 · 研究领域：Hearing, Cochlea, Tinnitus, Genetics、Vestibular and auditory disorders、Hearing Loss and Rehabilitation

Atonal homolog 1 (Atoh1) is a basic helix-loop-helix (bHLH) transcription factor that is essential for the genesis, survival, and maturation of a variety of neuronal and non-neuronal cell populations, including those involved in proprioception, interoception, balance, respiration, and hearing. Such diverse functions require fine regulation at the transcriptional and protein levels. Here, we show that serine 193 (S193) is phosphorylated in Atoh19s bHLH domain in vivo . Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background ( Atoh1 S193A/lacZ ) exhibit mild cerebellar foliation defects, motor impairments, partial pontine nucleus migration defects, cochlear hair cell degeneration, and profound hearing loss. We also found that Atoh1 heterozygous mice of both sexes ( Atoh1 lacZ/+ ) have adult-onset deafness. These data indicate that different cell types have different degrees of vulnerability to loss of Atoh1 function and that hypomorphic Atoh1 alleles should be considered in human hearing loss. SIGNIFICANCE STATEMENT The discovery that Atonal homolog 1 (Atoh1) governs the development of the sensory hair cells in the inner ear led to therapeutic efforts to restore these cells in cases of human deafness. Because prior studies of Atoh1 -heterozygous mice did not examine or report on hearing loss in mature animals, it has not been clinical practice to sequence ATOH1 in people with deafness. Here, in seeking to understand how phosph...