A New Mutation of the Atoh1 Gene in Mice with Normal Life Span Allows Analysis of Inner Ear and Cerebellar Phenotype in Aging

Kianoush Sheykholeslami,Sheng Li Li,Xiaohui Bai,Zhaoqiang Zhang,Casey Nava,Shuqing Liu,Vikrum Thimmappa,Tihua Zheng,Qing Yin Zheng,Heping Yu,Olivia Bermingham-Mcdonogh

doi:10.1371/journal.pone.0079791

Kianoush Sheykholeslami, Sheng Li Li + Show 9 more

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https://doi.org/10.1371/journal.pone.0079791

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Abstract

Atoh1 is a transcription factor that regulates neural development in multiple tissues and is conserved among species. Prior mouse models of Atoh1, though effective and important in the evolution of our understanding of the gene, have been limited by perinatal lethality. Here we describe a novel point mutation of Atoh1 (designated Atoh1trhl) underlying a phenotype of trembling gait and hearing loss. Histology revealed inner ear hair cell loss and cerebellar atrophy. Auditory Brainstem Response (ABR) and Distortion Product Otoacoustic Emission (DPOAE) showed functional abnormalities in the ear. Normal lifespan and fecundity of Atoh1trhlmice provide a complementary model to facilitate elucidation of ATOH1 function in hearing,central nervous system and cancer biology.

Highlights

Atoh1 (Math1), a basic helix-loop-helix transcription factor homolog of the Drosophilaatonal gene is involved in a wide range of developmental changes in mice and humans.A critical role in neurogenesis has been shown for Atoh1 in proper hindbrain development [1]
Homozygous mutant mice exhibit a shaky gait at weaning age and a progressive hearing loss starting at 3 weeks of age or earlier and culminating in near-total deafness by 8 months, with a lifespan that is comparable to wild-type mice
Since the trhl mutant mice have a normal life span, unlike previous Atoh1-nullmutations, which are perinatally lethal, we can take advantage of this newmodel to investigate many aspects of downstream hearing and balance pathophysiology, molecular biology, proteomics and cancer biology. We feel that this unique model can offer an interesting alternate pathway to examine Atoh1 function to complement other models and not necessarily replace them

Summary

Introduction

Atoh (Math1), a basic helix-loop-helix transcription factor homolog of the Drosophilaatonal gene is involved in a wide range of developmental changes in mice and humans.A critical role in neurogenesis has been shown for Atoh in proper hindbrain development [1]. Unconscious proprioception is dysfunctional in mice lacking Atoh, with cerebella missing the external granule layer and bereft of the granule cells essential for proper functioning [2]. Atoh has been implicated in the creation and interplay of complex neural circuits that link hearing, proprioception and arousal with tasks like respiration, likely through a pathway of glutamatergic neurons [1]. Atoh behavesas anoncogene in medullablastomas[4] but acts as a tumor suppressorgene in adenomatous polyposiscarcinoma[5]. The Atoh gene plays many significant roles in the development of several organs, systems and diseases

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