ATOH1
Protein atonal homolog 1 (Class A basic helix-loop-helix protein 14) (bHLHa14) (Helix-loop-helix protein hATH-1) (hATH1) [ATH1] [BHLHA14]
Publications[править]
Hearing loss is widespread and persistent because mature mammalian auditory hair cells (HCs) are nonregenerative. In mice, the ability to regenerate HCs from surrounding supporting cells (SCs) declines abruptly after postnatal maturation. We find that combining p27 deletion with ectopic ATOH1 expression surmounts this age-related decline, leading to conversion of SCs to HCs in mature mouse cochleae and after noise damage. p27 deletion, independent of canonical effects on Rb-family proteins, upregulated GATA3, a co-factor for ATOH1 that is lost from SCs with age. Co-activation of GATA3 or POU4F3 and ATOH1 promoted conversion of SCs to HCs in adult mice. Activation of POU4F3 alone also converted mature SCs to HCs in vivo. These data illuminate a genetic pathway that initiates auditory HC regeneration and suggest p27 , GATA3, and POU4F3 as additional therapeutic targets for ATOH1-mediated HC regeneration.
MeSH Terms
- Animals
- Animals, Newborn
- Basic Helix-Loop-Helix Transcription Factors
- Cell Proliferation
- Cochlea
- Cyclin-Dependent Kinase Inhibitor p27
- GATA3 Transcription Factor
- Gene Expression Regulation, Developmental
- Hair Cells, Auditory
- Hearing Loss
- Homeodomain Proteins
- Humans
- Mice
- Regeneration
- Signal Transduction
- Transcription Factor Brn-3C
Keywords
- aging
- cancer
- cochlea
- development
- differentiation
- hearing
- proliferation
- regeneration
- sensory
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 Atoh1(trhl) ) 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 Atoh1(trhl) mice provide a complementary model to facilitate elucidation of ATOH1 function in hearing,central nervous system and cancer biology.
MeSH Terms
- Aging
- Amino Acid Sequence
- Animals
- Basic Helix-Loop-Helix Transcription Factors
- Cerebellum
- Chromosome Mapping
- DNA Mutational Analysis
- Ear, Inner
- Gene Expression Regulation
- Hair Cells, Auditory, Inner
- Hearing Loss
- Hearing Tests
- Longevity
- Mice
- Mutation
- Phenotype
- RNA, Messenger
- Sequence Alignment
Inner ear hair cells have been suggested as attractors for growing afferent fibers, possibly through the release of the neurotrophin brain-derived neurotrophic factor (BDNF). Atoh1 null mice never fully differentiate hair cells and supporting cells and, therefore, may show aberrations in the growth and/or retention of their innervation. We investigated the distribution of cells positive for Atoh1- or Bdnf-mediated beta-galactosidase expression in Atoh1 null and Atoh1 heterozygotic mice and correlated the distribution of these cells with their innervation. Embryonic day (E) 18.5 Atoh1 null and heterozygotic littermates show Atoh1- and BDNF-beta-galactosidase-positive cells in comparable distributions in the canal cristae and the cochlea apex. Atoh1-beta-galactosidase-positive but only occasional Bdnf-beta-galactosidase-positive cells are found in the utricle, saccule, and cochlea base of Atoh1 null mutant mice. Absence of Bdnf-beta-galactosidase expression in the utricle and saccule of Atoh1 null mice is first noted at E12.5, a time when Atoh1-beta-galactosidase expression is also first detected in these epithelia. These data suggest that expression of Bdnf is dependent on ATOH1 protein in some but does not require ATOH1 protein in other inner ear cells. Overall, the undifferentiated Atoh1- and Bdnf-beta-galactosidase-positive cells show a distribution reminiscent of that in the six sensory epithelia in control mice, suggesting that ear patterning processes can form discrete patches of Atoh1 and Bdnf expression in the absence of ATOH1 protein. The almost normal growth of afferent and efferent fibers in younger embryos suggests that neither fully differentiated hair cells nor BDNF are necessary for the initial targeted growth of fibers. E18.5 Atoh1 null mice have many afferent fibers to the apex of the cochlea, the anterior and the posterior crista, all areas with numerous Bdnf-beta-galactosidase-positive cells. Few fibers remain to the saccule, utricle, and the base of the cochlea, all areas with few or no Bdnf-beta-galactosidase-positive cells. Thus, retention of fibers is possible with BDNF, even in the absence of differentiated hair cells.
MeSH Terms
- Aging
- Animals
- Basic Helix-Loop-Helix Transcription Factors
- Body Patterning
- Brain-Derived Neurotrophic Factor
- Cell Differentiation
- Coloring Agents
- DNA-Binding Proteins
- Ear
- Epithelium
- Gene Expression Regulation, Developmental
- Hair Cells, Auditory
- Heterozygote
- Hydrophobic and Hydrophilic Interactions
- Lac Operon
- Lipids
- Mice
- Mice, Knockout
- Nerve Tissue Proteins
- Neurons, Afferent
- Transcription Factors
Keywords Non-programmatic