Journal
MOLECULAR NEUROBIOLOGY
Volume 53, Issue 4, Pages 2421-2434Publisher
HUMANA PRESS INC
DOI: 10.1007/s12035-015-9206-2
Keywords
LSD1; Zebrafish; Hair cell; Regeneration; Fgf signaling pathway; Wnt signaling pathway
Categories
Funding
- Major State Basic Research Development Program of China (973 Program) [2011CB504506]
- Young Scientist 973 Project [2015CB965000]
- National Natural Science Foundation of China [81230019, 81470687, 81470692]
- Program for Changjiang Scholars and Innovative Research Team in Universities [IRT1010]
- Jiangsu Province Natural Science Foundation [BK20140620]
- Specialized Research Fund for the Doctor Program of Higher Education [20120071110077]
- Fundamental Research Funds for the Central Universities [2242014R30022, NO2013WSN085]
- Construction Program of Shanghai Committee of Science and Technology [12DZ2251700]
- Major Program of Shanghai Committee of Science and Technology [11441901000]
- China Postdoctoral Science Foundation Funded Project [2014M551328]
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Lysine-specific demethylase 1 (LSD1/KDM1A) plays an important role in complex cellular processes such as differentiation, proliferation, apoptosis, and cell cycle progression. It has recently been demonstrated that during development, downregulation of LSD1 inhibits cell proliferation, modulates the expression of cell cycle regulators, and reduces hair cell formation in the zebrafish lateral line, which suggests that LSD1-mediated epigenetic regulation plays a key role in the development of hair cells. However, the role of LSD1 in hair cell regeneration after hair cell loss remains poorly understood. Here, we demonstrate the effect of LSD1 on hair cell regeneration following neomycin-induced hair cell loss. We show that the LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA) significantly decreases the regeneration of hair cells in zebrafish after neomycin damage. In addition, immunofluorescent staining demonstrates that 2-PCPA administration suppresses supporting cell proliferation and alters cell cycle progression. Finally, in situ hybridization shows that 2-PCPA significantly downregulates the expression of genes related to Wnt/beta-catenin and Fgf activation. Altogether, our data suggest that downregulation of LSD1 significantly decreases hair cell regeneration after neomycin-induced hair cell loss through inactivation of the Wnt/beta-catenin and Fgf signaling pathways. Thus, LSD1 plays a critical role in hair cell regeneration and might represent a novel biomarker and potential therapeutic approach for the treatment of hearing loss.
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