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LSD1 is Required for Hair Cell Regeneration in Zebrafish

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Abstract

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/β-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/β-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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Acknowledgments

The authors would like to thank Dong Liu, Min Yu, and Shaoyang Sun for their technical assistance and Yalin Huang for the help with the confocal microscope. This work was supported by grants from the Major State Basic Research Development Program of China (973 Program) (2011CB504506), the Young Scientist 973 Project (2015CB965000), the National Natural Science Foundation of China (Nos. 81230019, 81470687, 81470692), the Program for Changjiang Scholars and Innovative Research Team in Universities (IRT1010), the Jiangsu Province Natural Science Foundation (BK20140620), the Specialized Research Fund for the Doctor Program of Higher Education (20120071110077), the Fundamental Research Funds for the Central Universities (2242014R30022, NO2013WSN085), the Construction Program of Shanghai Committee of Science and Technology (12DZ2251700), the Major Program of Shanghai Committee of Science and Technology (11441901000), and the China Postdoctoral Science Foundation Funded Project (2014M551328).

Conflict of Interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Otorhinolaryngology, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, 200031, People’s Republic of China

    Yingzi He, Dongmei Tang & Huawei Li

  2. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, People’s Republic of China

    Huawei Li

  3. Institute of Stem Cell and Regeneration Medicine, Institute of Biomedical Science, Fudan University, Shanghai, People’s Republic of China

    Huawei Li

  4. Key Laboratory of Hearing Science, Ministry of Health, EENT Hospital, Fudan University, Shanghai, People’s Republic of China

    Huawei Li

  5. Co-innovation Center of Neuroregeneration, Key Laboratory for Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, 210096, People’s Republic of China

    Renjie Chai

  6. Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, People’s Republic of China

    Chengfu Cai

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  2. Dongmei Tang
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  3. Chengfu Cai
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  4. Renjie Chai
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  5. Huawei Li
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Corresponding author

Correspondence to Huawei Li.

Additional information

Yingzi He and Dongmei Tang contributed equally to this work.

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Supplemental Figure 1

Effects of 2-PCPA on apoptosis. 5-dpf zebrafish were treated with neomycin for 1 h and then incubated for 12 or 48 h with 100 μM 2-PCPA. Protein extracts were prepared and subjected to western blotting assay using an antibody against cleaved caspase-3. β-Actin was included as the control. (DOCX 103 kb)

Supplemental table

Primers used in the study (DOCX 38 kb)

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He, Y., Tang, D., Cai, C. et al. LSD1 is Required for Hair Cell Regeneration in Zebrafish. Mol Neurobiol 53, 2421–2434 (2016). https://doi.org/10.1007/s12035-015-9206-2

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  • DOI: https://doi.org/10.1007/s12035-015-9206-2

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