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

J Neurosci. 2017 Sep 6;37(36):8583-8594. doi: 10.1523/JNEUROSCI.0295-17.2017. Epub 2017 Jul 20.

Abstract

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 Atoh1's bHLH domain in vivo Knock-in mice of both sexes bearing a GFP-tagged phospho-dead S193A allele on a null background (Atoh1S193A/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 (Atoh1lacZ/+) 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 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.

Keywords: Atoh1; Math1; hearing loss; inner ear; phosphorylation; ponti nucleus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Aging / pathology
  • Alleles*
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Female
  • Gene Knock-In Techniques
  • Genetic Predisposition to Disease / genetics*
  • Hair Cells, Auditory / pathology*
  • Hearing Loss / genetics*
  • Hearing Loss / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Movement Disorders / genetics*
  • Movement Disorders / pathology
  • Mutation, Missense / genetics
  • Serine / genetics

Substances

  • Atoh1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Serine