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Hum Mol Genet. 2018 Mar 1;27(5):860-874. doi: 10.1093/hmg/ddy007.

miR-96 is required for normal development of the auditory hindbrain.

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Neurogenetics Group, Center of Excellence Hearing4All, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
Division of Neurobiology, Department Biology II, Ludwig-Maximilians University Munich, 82152 Martinsried, Germany.
Computational Theoretical Physics Group, Institute of Physics, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.
Institute of Zoology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany.
Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.


The peripheral deafness gene Mir96 is expressed in both the cochlea and central auditory circuits. To investigate whether it plays a role in the auditory system beyond the cochlea, we characterized homozygous Dmdo/Dmdo mice with a point mutation in miR-96. Anatomical analysis demonstrated a significant decrease in volume of auditory nuclei in Dmdo/Dmdo mice. This decrease resulted from decreased cell size. Non-auditory structures in the brainstem of Dmdo/Dmdo mice or auditory nuclei of the congenital deaf Cldn14-/- mice revealed no such differences. Electrophysiological analysis in the medial nucleus of the trapezoid body (MNTB) showed that principal neurons fired preferentially multiple action potentials upon depolarization, in contrast to the single firing pattern prevalent in controls and Cldn14-/- mice. Immunohistochemistry identified significantly reduced expression of two predicted targets of the mutated miR-96, Kv1.6 and BK channel proteins, possibly contributing to the electrophysiological phenotype. Microscopic analysis of the Dmdo/Dmdo calyx of Held revealed a largely absent compartmentalized morphology, as judged by SV2-labeling. Furthermore, MNTB neurons from Dmdo/Dmdo mice displayed larger synaptic short-term depression, slower AMPA-receptor decay kinetics and a larger NMDA-receptor component, reflecting a less matured stage. Again, these synaptic differences were not present between controls and Cldn14-/- mice. Thus, deafness genes differentially affect the auditory brainstem. Furthermore, our study identifies miR-96 as an essential gene regulatory network element of the auditory system which is required for functional maturation in the peripheral and central auditory system alike.

[Indexed for MEDLINE]

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