title: Response of the flat cochlear epithelium to forced expression of Atoh1.
abstract: Following hair cell elimination in severely traumatized cochleae, differentiated supporting cells are often replaced by a simple epithelium with cuboidal or flat appearance. Atoh1 (previously Math1) is a basic helix-loop-helix transcription factor critical to hair cell differentiation during mammalian embryogenesis. Forced expression of Atoh1 in the differentiated supporting cell population can induce transdifferentiation leading to hair cell regeneration. Here, we examined the outcome of adenovirus mediated over-expression of Atoh1 in the non-sensory cells of the flat epithelium. We determined that seven days after unilateral elimination of hair cells with neomycin, differentiated supporting cells are absent, replaced by a flat epithelium. Nerve processes were also missing from the auditory epithelium, with the exception of infrequent looping nerve processes above the habenula perforata. We then inoculated an adenovirus vector with Atoh1 insert into the scala media of the deafened cochlea. The inoculation resulted in upregulation of Atoh1 in the flat epithelium. However, two months after the inoculation, Atoh1-treated ears did not exhibit clear signs of hair cell regeneration. Combined with previous data on induction of supporting cell to hair cell transdifferentiation by forced expression of Atoh1, these results suggest that the presence of differentiated supporting cells in the organ of Corti is necessary for transdifferentiation to occur.
authors.affiliation: Kresge Hearing Research Institute, The University of Michigan Medical School, Ann Arbor, MI 48109-5648, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Izumikawa
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Batts
authors.forename: Toru
authors.initials: T
authors.lastname: Miyazawa
authors.forename: Donald L
authors.initials: DL
authors.lastname: Swiderski
authors.forename: Yehoash
authors.initials: Y
authors.lastname: Raphael
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D048430:Cell Shape; D054338:Cell Transdifferentiation; D003051:Cochlea / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000378:metabolism / Q000648:ultrastructure; D046088:Hearing Loss, Unilateral / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007760:Labyrinth Supporting Cells / Q000378:metabolism / Q000648:ultrastructure; D009355:Neomycin; D012038:Regeneration; D013997:Time Factors; D014161:Transduction, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D009355:Neomycin; C500943:Atoh1 protein, mouse