Wei Guanyun, Zhang Xu, Cai Chengyun, Sheng Jiajing, Xu Mengting, Wang Cheng, Gu Qiuxiang, Guo Chao, Chen Fangyi, Liu Dong, Qian Fuping
Key Laboratory of Neuroregeneration of MOE, Nantong Laboratory of Development and Diseases, School of Life Sciences, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Translational Medical Research Center, Wuxi No. 2 People's Hospital, Affiliated Wuxi Clinical College of Nantong University, Wuxi, China.
Front Cell Neurosci. 2022 Mar 23;16:840143. doi: 10.3389/fncel.2022.840143. eCollection 2022.
Most cases of acquired hearing loss are due to degeneration and subsequent loss of cochlear hair cells. Whereas mammalian hair cells are not replaced when lost, in zebrafish, they constantly renew and regenerate after injury. However, the molecular mechanism among this difference remains unknown. Dual-specificity phosphatase 14 (DUSP14) is an important negative modulator of mitogen-activated protein kinase (MAPK) signaling pathways. Our study was to investigate the effects of DUSP14 on supporting cell development and hair cell regeneration and explore the potential mechanism. Our results showed that gene is highly expressed in zebrafish developing neuromasts and otic vesicles. Behavior analysis showed that deficiency resulted in hearing defects in zebrafish larvae, which were reversed by mRNA treatment. Moreover, knockdown of gene caused a significant decrease in the number of neuromasts and hair cells in both neuromast and otic vesicle, mainly due to the inhibition of the proliferation of supporting cells, which results in a decrease in the number of supporting cells and ultimately in the regeneration of hair cells. We further found significant changes in a series of MAPK pathway genes through transcriptome sequencing analysis of -deficient zebrafish, especially gene in p38 signaling. Additionally, inhibiting p38 signaling effectively rescued all phenotypes caused by deficiency, including hair cell and supporting cell reduction. These results suggest that DUSP14 might be a key gene to regulate supporting cell development and hair cell regeneration and is a potential target for the treatment of hearing loss.
大多数获得性听力损失病例是由于耳蜗毛细胞退化并随后丧失所致。哺乳动物的毛细胞丧失后无法替换，而斑马鱼的毛细胞在受损后能持续更新和再生。然而，这种差异背后的分子机制仍不清楚。双特异性磷酸酶14（DUSP14）是丝裂原活化蛋白激酶（MAPK）信号通路的重要负性调节因子。我们的研究旨在探讨DUSP14对支持细胞发育和毛细胞再生的影响，并探索其潜在机制。我们的结果表明，该基因在斑马鱼发育中的神经丘和耳囊中高表达。行为分析表明，该基因缺陷导致斑马鱼幼体出现听力缺陷，而通过该基因的mRNA处理可使其逆转。此外，敲低该基因导致神经丘和耳囊中神经丘和毛细胞数量显著减少，主要是由于支持细胞增殖受到抑制，这导致支持细胞数量减少，最终影响毛细胞再生。通过对该基因缺陷斑马鱼的转录组测序分析，我们进一步发现一系列MAPK通路基因发生了显著变化，尤其是p38信号通路中的某个基因。此外，抑制p38信号通路可有效挽救该基因缺陷导致的所有表型，包括毛细胞和支持细胞数量减少。这些结果表明，DUSP14可能是调节支持细胞发育和毛细胞再生的关键基因，是治疗听力损失的潜在靶点。
