Identification of modulators of hair cell regeneration in the zebrafish lateral line
- Authors
- Namdaran, P., Reinhart, K.E., Owens, K.N., Raible, D.W., and Rubel, E.W.
- ID
- ZDB-PUB-120314-9
- Date
- 2012
- Source
- The Journal of neuroscience : the official journal of the Society for Neuroscience 32(10): 3516-3528 (Journal)
- Registered Authors
- Owens, Kelly, Raible, David
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Death/drug effects
- Cell Death/physiology
- Estradiol/analogs & derivatives
- Estradiol/pharmacology
- Glucocorticoids/pharmacology
- Hair Cells, Auditory/drug effects
- Hair Cells, Auditory/physiology*
- Lateral Line System/cytology
- Lateral Line System/drug effects
- Lateral Line System/physiology*
- Mebendazole/analogs & derivatives
- Mebendazole/pharmacology
- Mechanoreceptors/drug effects
- Mechanoreceptors/physiology
- Neomycin/pharmacology
- Nerve Regeneration/drug effects
- Nerve Regeneration/physiology*
- Neural Inhibition/drug effects
- Stem Cells/cytology
- Stem Cells/drug effects
- Stem Cells/physiology
- Topotecan/pharmacology
- Zebrafish
- PubMed
- 22399774 Full text @ J. Neurosci.
The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory hair cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate hair cell regeneration in zebrafish. Of the 1680 compounds evaluated, we identified two enhancers and six inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated hair cell numbers during regeneration and also induced hair cell addition in the absence of damage. BrdU analysis confirmed that the extra hair cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that hair cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress hair cell regeneration by preventing proliferation of hair cell precursors. Flubendazole halted support cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both hair cells and proliferating hair cell precursors. A third inhibitor, fulvestrant, moderately delayed hair cell regeneration by reducing support cell proliferation. Our observation that hair cells do not regenerate when support cell proliferation is impeded confirms previous observations that cell division is the primary route for hair cell regeneration after neomycin treatment in zebrafish.