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The Journal of Neuroscience, February 27, 2008, 28(9):2261-2273; doi:10.1523/JNEUROSCI.4372-07.2008

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Development/Plasticity/Repair
Notch Signaling Regulates the Extent of Hair Cell Regeneration in the Zebrafish Lateral Line

Eva Y. Ma,^1,2 Edwin W Rubel,^3,4,5 and David W. Raible^1,2,3

¹Molecular and Cellular Biology Program, ²Department of Biological Structure, ³Virginia Merrill Bloedel Hearing Research Center, ⁴Department of Otolaryngology–Head and Neck Surgery, and ⁵Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195-7420

Correspondence should be addressed to David W. Raible, Department of Biological Structure, University of Washington, Box 357420, Seattle, WA 98195-7420. Email: draible{at}u.washington.edu

Mechanosensory hair cells within the zebrafish lateral line spontaneously regenerate after aminoglycoside-induced death. Exposure of 5-d-old larvae to 400 µM neomycin for 1 h results in death of almost all lateral line hair cells. Regeneration of new hair cells is observed by 24 h after neomycin treatment with nearly complete replacement by 72 h. Using bromodeoxyuridine incorporation, we show that the majority of new hair cells are generated from a transient increase in support cell proliferation that occurs between 12 and 21 h after neomycin damage. Additional observations reveal two distinct subsets of proliferating support cells within the neuromasts that differ in position, morphology, and temporal pattern of proliferation in response to neomycin exposure. We hypothesize that proliferative hair cell progenitors are located centrally within the neuromasts, whereas peripheral support cells may have a separate function. Expression of Notch signaling pathway members notch3, deltaA, and atoh1a transcripts are all upregulated within the first 24 h after neomycin treatment, during the time of maximum proliferation of support cells and hair cell progenitor formation. Treatment with a -secretase inhibitor results in excess regenerated hair cells by 48 h after neomycin-induced death but has no effect without previous damage. Excess hair cells result from increased support cell proliferation. These results suggest a model where Notch signaling limits the number of hair cells produced during regeneration by regulating support cell proliferation.

Key words: lateral line; Notch; hair cell regeneration; support cell proliferation; zebrafish; aminoglycoside

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Received Sept. 24, 2007; revised Dec. 20, 2007; accepted Dec. 24, 2007.

Correspondence should be addressed to David W. Raible, Department of Biological Structure, University of Washington, Box 357420, Seattle, WA 98195-7420. Email: draible{at}u.washington.edu

This article has been cited by other articles:

				D. A. Prober, S. Zimmerman, B. R. Myers, B. M. McDermott Jr, S.-H. Kim, S. Caron, J. Rihel, L. Solnica-Krezel, D. Julius, A. J. Hudspeth, et al. Zebrafish TRPA1 Channels Are Required for Chemosensation But Not for Thermosensation or Mechanosensory Hair Cell Function J. Neurosci., October 1, 2008; 28(40): 10102 - 10110. [Abstract] [Full Text] [PDF]

				W. J. Van Trump and M. J. McHenry The morphology and mechanical sensitivity of lateral line receptors in zebrafish larvae (Danio rerio) J. Exp. Biol., July 1, 2008; 211(13): 2105 - 2115. [Abstract] [Full Text] [PDF]

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