Liu Fei, Yang Fan, Wen Danping, Xia Wenjun, Hao Lili, Hu JiongJiong, Zong Jie, Shen Xiaofang, Ma Jing, Jiang Nan, Sun Shaoyang, Zhang Jin, Wang Huijun, Wang Xu, Ma Zhaoxin, Ma Duan
Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Int J Dev Biol. 2015;59(10-12):417-23. doi: 10.1387/ijdb.140230FL.
Many genes that have been found to contribute to deafness are currently being studied. Some 87 non-syndromic hereditary deafness genes have been confirmed. Proteins associated with cochlear development have also been confirmed. Some of these proteins have important relationships with gap junctions (GJ) and tight junctions (TJ). However, the desmosome junction has received little attention due to controversy over whether it could be detected in the inner ear. GRHL1 is a conserved transcriptional regulator, and it is key to vertebrate desmosome formation. GRHL2 has been confirmed as a deafness gene at the DFNA28 locus. These two homologous proteins have similar sequences and functions. Here, a grhl1 down-regulated zebrafish model exhibited inner ear developmental malformations, including missing otoliths, disordered and abnormal numbers of hair cells in the inner ear and lateral line, and sound insensitivity. The mutant zebrafish swam in circles. Hair cell apoptosis was evident. Under electron microscopy, desmosomes in the otic sensory epithelium were found to be damaged. These defects were partially rescued by treatment with either GRHL1 or its target gene, DSG1. Collectively, these data are the first to indicate that grhl1 is important to the developing inner ear epithelia in zebrafish and that it acts via desmosome junction regulation.
目前正在研究许多已被发现与耳聋有关的基因。已确认约87个非综合征性遗传性耳聋基因。与耳蜗发育相关的蛋白质也已得到确认。其中一些蛋白质与缝隙连接（GJ）和紧密连接（TJ）有重要关系。然而，由于关于是否能在内耳中检测到桥粒连接存在争议，桥粒连接受到的关注较少。GRHL1是一种保守的转录调节因子，是脊椎动物桥粒形成的关键。GRHL2已被确认为DFNA28位点的耳聋基因。这两种同源蛋白具有相似的序列和功能。在此，一个grhl1下调的斑马鱼模型表现出内耳发育畸形，包括耳石缺失、内耳和侧线中毛细胞数量紊乱和异常，以及声音不敏感。突变斑马鱼会转圈游动。毛细胞凋亡明显。在电子显微镜下，发现耳感觉上皮中的桥粒受损。用GRHL1或其靶基因DSG1处理可部分挽救这些缺陷。总的来说，这些数据首次表明grhl1对斑马鱼发育中的内耳上皮很重要，并且它通过桥粒连接调节发挥作用。
