An Atoh1-S193A phospho-mutant allele causes hearing deficits and motor impairment.

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An Atoh1-S193A phospho-mutant allele causes hearing deficits and motor impairment.

J Neurosci. 2017 Jul 20;:

Authors: Rose Xie W, Jen HI, Seymour ML, Yeh SY, Pereira FA, Groves AK, Klisch TJ, Zoghbi HY

Abstract
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 Atoh1's 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, and also 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 STATEMENTThe discovery that 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 nor 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 phosphorylation of Atoh1 modulates its effects in vivo, we discovered that inner ear hair cells are much more vulnerable to loss of Atoh1 function than other Atoh1-positive cell types, and that heterozygous mice actually develop hearing loss late in life. This opens up the possibility that missense mutations in ATOH1 could increase human vulnerability to loss of hair cells because of aging or trauma.

PMID: 28729444 [PubMed - as supplied by publisher]

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