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The Journal of Neuroscience, April 18, 2007, 27(16):4313-4325; doi:10.1523/JNEUROSCI.5023-06.2007
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Development/Plasticity/Repair
Shape Change Controls Supporting Cell Proliferation in Lesioned Mammalian Balance Epithelium
Jason R. Meyers andJeffrey T. Corwin Neuroscience Graduate Program and Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22908
Correspondence should be addressed to Jason R. Meyers at his present address: Molecular Cellular and Developmental Biology, University of Michigan, 830 North University Street, Ann Arbor, MI 48109-1048. Email: jrmeyers{at}umich.edu
Mature mammals are uniquely vulnerable to permanent auditory and vestibular deficits, because the cell proliferation that produces replacement hair cells in other vertebrates is limited in mammals. To investigate the cellular mechanisms responsible for that difference, we created excision lesions in the sensory epithelium of embryonic and 2-week-old mouse utricles. Lesions in embryonic utricles closed in <24 h via localized expansion of supporting cells, which then reentered the cell cycle. Pharmacological treatments combined with time-lapse microscopy demonstrated that the healing depended on Rho-mediated contraction of an actin ring at the leading edge of the lesion. In contrast, lesions in utricles from 2-week-old and older mice remained open even after 48 h. Supporting cells in those utricles remained compact and columnar and had significantly stouter cortical actin belts than those in embryonic sensory epithelia. This suggests that cytoskeletal changes may underlie the age-related loss of proliferation in mammalian ears by limiting the capacity for mature supporting cells to change shape. In mature utricles, exogenous stimulation with lysophosphatidic acid overcame this maturational block and induced closure of lesions, promoting supporting cell expansion and subsequent proliferation. After lysophosphatidic acid treatment, 85% of the mature supporting cells that had spread to a planar area >300 µm2 entered S-phase, whereas only 10% of those cells that had a planar area <100 µm2 entered S-phase. Together, these results indicate that cellular shape change can overcome the normal postnatal cessation of supporting cell proliferation that appears to limit regeneration in mammalian vestibular epithelia.
Key words: hair cell; regeneration; lysophosphatidic acid; LPA; vestibular; wound healing; cytoskeleton
Received Nov. 20, 2006; revised Feb. 19, 2007; accepted March 15, 2007.
Correspondence should be addressed to Jason R. Meyers at his present address: Molecular Cellular and Developmental Biology, University of Michigan, 830 North University Street, Ann Arbor, MI 48109-1048. Email: jrmeyers{at}umich.edu
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