title: Developmental changes in cell-extracellular matrix interactions limit proliferation in the mammalian inner ear.
abstract: Hair cell losses can produce severe hearing and balance deficits in mammals and nonmammals alike, but nonmammals recover after epithelial supporting cells divide and give rise to replacement hair cells. Here, we describe cellular changes that appear to underlie the permanence of hair cell deficits in mammalian vestibular organs. In sensory epithelia isolated from the utricles of embryonic day 18 (E18) mice, supporting cells readily spread and proliferated, but spreading and proliferation were infrequent in supporting cells from postnatal day 6 (P6) mice. Cellular spreading and proliferation were dependent on alpha6 integrin, which disappeared from lateral cell membranes by P6 and colocalized with beta4 integrin near the basement membrane at both ages. In the many well-spread, proliferating E18 supporting cells, beta4 was localized at cell borders, but it was localized to hemidesmosome-like structures in the columnar, nondividing supporting cells that were prevalent in P6 cultures. We treated cultures with phorbol myristate acetate (PMA) to activate protein kinase C (PKC) in an initial test of the possibility that maturational changes in supporting cell cytoskeletons or their anchorage might restrict the proliferation of these progenitor cells in the developing mammalian inner ear. That treatment triggered the disassembly of the hemidesmosome-like beta4 structures and resulted in significantly increased cellular spreading and S-phase entry in the P6 epithelia. The results suggest that maturational changes in cytoskeletal organization and anchorage restrict proliferation of mammalian supporting cells whose counterparts are the progenitors of replacement hair cells in nonmammals, thereby leaving mammals vulnerable to persistent sensory deficits caused by hair cell loss.
authors.affiliation: Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. dawn.davies@bristol.ac.uk
authors.forename: Dawn
authors.initials: D
authors.lastname: Davies
authors.forename: Christopher
authors.initials: C
authors.lastname: Magnus
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Corwin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D003599:Cytoskeleton / Q000378:metabolism; D007758:Ear, Inner / Q000166:cytology* / Q000196:embryology*; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000502:physiology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism*; D006198:Hair Cells, Auditory / Q000502:physiology*; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009924:Organ Culture Techniques; D012444:Saccule and Utricle / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D001973:Bromodeoxyuridine; D013755:Tetradecanoylphorbol Acetate