Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Mingshun Lu
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Shengnan Wang
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Xueya Ma
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Fei Wang
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Jiaxi Liu
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Xinyu Li
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Haichao Yang
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Fan Zhang
Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China
Haitao Shen
Lab of Pathology, Hebei Medical University, Shijiazhuang, China
Noel J Buckley
Department of Psychiatry, University of Oxford, Oxford, United Kingdom; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, United Kingdom
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
Department of Pharmacology, The Key Laboratory of New Drug Pharmacology and Toxicology, Hebei Medical University, Shijiazhuang, China; Center for Innovative Drug Research and Evaluation, Institute of Medical Science and Health, Hebei Medical University, Shijiazhuang, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China; The Hebei Collaboration Innovation Center for Mechanism, Diagnosis and Treatment of Neurological and Psychiatric Disease, Hebei Medical University, Shijiazhuang, China
Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons [SGNs]). Null inactivation of full-length REST did not affect the development of normal HCs and SGNs but manifested as progressive hearing loss in adult mice. We found that the inactivation of REST resulted in an increased abundance of Kv7.4 channels at the transcript, protein, and functional levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased Kv7.4 expression and augmented Kv7 currents; SGN’s excitability was also significantly reduced. Administration of a compound with Kv7.4 channel activator activity, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the Kv7 channels by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the Kv7.4-coding gene, Kcnq4, as a causative factor for progressive hearing loss in mice and humans. Thus, the findings reveal that a critical homeostatic Kv7.4 channel level is required for proper auditory functions.
