Harris Suzan L, Kazmierczak Marcin, Pangršič Tina, Shah Prahar, Chuchvara Nadiya, Barrantes-Freer Alonso, Moser Tobias, Schwander Martin
Department of Cell Biology and Neuroscience, Rutgers the State University of New Jersey, Piscataway, NJ 08854, United States.
Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, 37099 Göttingen, Germany; Collaborative Research Center 889, University of Göttingen, 37099 Göttingen, Germany.
Neuroscience. 2017 Mar 6;344:380-393. doi: 10.1016/j.neuroscience.2016.12.055. Epub 2017 Jan 9.
Mutations in the Pejvakin (Pjvk) gene cause autosomal recessive hearing loss DFNB59 with audiological features of auditory neuropathy spectrum disorder (ANSD) or cochlear dysfunction. The precise mechanisms underlying the variable clinical phenotypes of DFNB59 remain unclear. Here, we demonstrate that mice with conditional ablation of the Pjvk gene in all sensory hair cells or only in outer hair cells (OHCs) show similar auditory phenotypes with early-onset profound hearing loss. By contrast, loss of Pjvk in adult OHCs causes a slowly progressive hearing loss associated with OHC degeneration and delayed loss of inner hair cells (IHCs), indicating a primary role for pejvakin in regulating OHC function and survival. Consistent with this model, synaptic transmission at the IHC ribbon synapse is largely unaffected in sirtaki mice that carry a C-terminal deletion mutation in Pjvk. Using the C-terminal domain of pejvakin as bait, we identified in a cochlear cDNA library ROCK2, an effector for the small GTPase Rho, and the scaffold protein IQGAP1, involved in modulating actin dynamics. Both ROCK2 and IQGAP1 associate via their coiled-coil domains with pejvakin. We conclude that pejvakin is required to sustain OHC activity and survival in a cell-autonomous manner likely involving regulation of Rho signaling.
佩贾金（Pjvk）基因突变会导致常染色体隐性听力损失DFNB59，具有听觉神经病谱系障碍（ANSD）或耳蜗功能障碍的听力学特征。DFNB59临床表型各异的精确机制仍不清楚。在此，我们证明，在所有感觉毛细胞或仅在外毛细胞（OHC）中条件性敲除Pjvk基因的小鼠表现出相似的听觉表型，伴有早发性重度听力损失。相比之下，成年OHC中Pjvk缺失会导致与OHC退化和内毛细胞（IHC）延迟丧失相关的缓慢进行性听力损失，这表明佩贾金在调节OHC功能和存活中起主要作用。与该模型一致，在Pjvk中携带C末端缺失突变的sirtaki小鼠中，IHC带状突触处的突触传递基本未受影响。以佩贾金的C末端结构域为诱饵，我们在耳蜗cDNA文库中鉴定出Rho相关卷曲螺旋蛋白激酶2（ROCK2），一种小GTP酶Rho的效应器，以及支架蛋白IQGAP1，它们参与调节肌动蛋白动力学。ROCK2和IQGAP1均通过其卷曲螺旋结构域与佩贾金结合。我们得出结论，佩贾金对于以细胞自主方式维持OHC活性和存活是必需的，这可能涉及Rho信号传导的调节。
