TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing
TRIOBP-5 sculpts stereocilia rootlets and stiffens supporting cells enabling hearing
复制标题
DOI：
10.1172/jci.insight.128561
复制
发表时间：
2019-06-20
期刊：
影响因子：
8
通讯作者：
Kitajiri, Shin-ichiro
中科院分区：
文献类型：
--
作者：
Katsuno, Tatsuya;Belyantseva, Inna A.;Kitajiri, Shin-ichiro
TRIOBP通过形成异常密集的F-肌动蛋白束重塑细胞骨架，并与人类癌症、精神分裂症和耳聋有关。切除人和小鼠TRIOBP-4和TRIOBP-5同种型的突变与深度耳聋相关，因为内耳机械感觉毛细胞在静纤毛根未能发育后退化。然而，每个TRIOBP亚型调节静纤毛根形成的机制仍然未知。使用3个新的Triobp小鼠模型，我们报告说，TRIOBP-5是必不可少的增厚束的F-肌动蛋白的根，建立其成熟的尺寸和硬化支持细胞的听觉感觉上皮。这种亚型的卷曲螺旋结构域是静纤毛根的加强和维持所必需的。小鼠中TRIOBP-5的缺失导致畸形小根，其在表皮板中异常薄，但在静纤毛核心内具有增加的宽度和长度，并导致重现人类表型的进行性耳聋。我们的研究扩展了目前对终身听力所必需的TRIOBP亚型特异性功能的理解，并对深入了解其他TRIOBP疾病产生了影响。
TRIOBP remodels the cytoskeleton by forming unusually dense F-actin bundles and is implicated in human cancer, schizophrenia, and deafness. Mutations ablating human and mouse TRIOBP-4 and TRIOBP-5 isoforms are associated with profound deafness, as inner ear mechanosensory hair cells degenerate after stereocilia rootlets fail to develop. However, the mechanisms regulating formation of stereocilia rootlets by each TRIOBP isoform remain unknown. Using 3 new Triobp mouse models, we report that TRIOBP-5 is essential for thickening bundles of F-actin in rootlets, establishing their mature dimensions and for stiffening supporting cells of the auditory sensory epithelium. The coiled-coil domains of this isoform are required for reinforcement and maintenance of stereocilia rootlets. A loss of TRIOBP-5 in mouse results in dysmorphic rootlets that are abnormally thin in the cuticular plate but have increased widths and lengths within stereocilia cores, and causes progressive deafness recapitulating the human phenotype. Our study extends the current understanding of TRIOBP isoform-specific functions necessary for life-long hearing, with implications for insight into other TRIOBPopathies.