94
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      An ENU-induced mutation of miR-96 associated with progressive hearing loss in mice

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Progressive hearing loss is common in the human population, but little is known about the molecular basis. We report a new ENU-induced mouse mutant, diminuendo, with a single base change in the seed region of Mirn96. Heterozygotes show progressive loss of hearing and hair cell anomalies, while homozygotes have no cochlear responses. Most microRNAs are believed to downregulate target genes by binding to specific sites on their mRNAs, so mutation of the seed should lead to target gene upregulation. Microarray analysis revealed 96 transcripts with significantly altered expression in homozygotes; notably, Slc26a5, oncomodulin, Gfi1, Ptprq and Pitpnm1 were downregulated. Hypergeometric p-value analysis showed hundreds of genes were upregulated in mutants. Different genes, with target sites complementary to the mutant seed, were downregulated. This is the first microRNA found associated with deafness, and diminuendo represents a model for understanding and potentially moderating progressive hair cell degeneration in hearing loss more generally.

          Related collections

          Most cited references27

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          MicroRNA Targets in Drosophila

          Additional data files Additional data file 1, 2, 3 and 4. Supplementary Material Additional data file 1 Additional data file 1 Click here for additional data file Additional data file 2 Additional data file 2 Click here for additional data file Additional data file 3 Additional data file 3 Click here for additional data file Additional data file 4 Additional data file 4 Click here for additional data file
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier.

            Hearing sensitivity in mammals is enhanced by more than 40 dB (that is, 100-fold) by mechanical amplification thought to be generated by one class of cochlear sensory cells, the outer hair cells. In addition to the mechano-electrical transduction required for auditory sensation, mammalian outer hair cells also perform electromechanical transduction, whereby transmembrane voltage drives cellular length changes at audio frequencies in vitro. This electromotility is thought to arise through voltage-gated conformational changes in a membrane protein, and prestin has been proposed as this molecular motor. Here we show that targeted deletion of prestin in mice results in loss of outer hair cell electromotility in vitro and a 40-60 dB loss of cochlear sensitivity in vivo, without disruption of mechano-electrical transduction in outer hair cells. In heterozygotes, electromotility is halved and there is a twofold (about 6 dB) increase in cochlear thresholds. These results suggest that prestin is indeed the motor protein, that there is a simple and direct coupling between electromotility and cochlear amplification, and that there is no need to invoke additional active processes to explain cochlear sensitivity in the mammalian ear.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              MicroRNA (miRNA) transcriptome of mouse retina and identification of a sensory organ-specific miRNA cluster.

              Although microRNAs (miRNAs) provide a newly recognized level of regulation of gene expression, the miRNA transcriptome of the retina and the contributions of miRNAs to retinal development and function are largely unknown. To begin to understand the functions of miRNAs in retina, we compared miRNA expression profiles in adult mouse retina, brain, and heart by microarray analysis. Our results show that at least 78 miRNAs are expressed in adult mouse retina, 21 of which are potentially retina-specific. Among these, we identified a polycistronic, sensory organ-specific paralogous miRNA cluster that includes miR-96, miR-182, and miR-183 on mouse chromosome 6qA3 with conservation of synteny to human chromosome 7q32.2. In situ hybridization showed that members of this cluster are expressed in photoreceptors, retinal bipolar and amacrine cells. Consistent with their genomic organization, these miRNAs have a similar expression pattern during development with abundance increasing postnatally and peaking in adult retina. Target prediction and in vitro functional studies showed that MITF, a transcription factor required for the establishment and maintenance of retinal pigmented epithelium, is a direct target of miR-96 and miR-182. Additionally, to identify miRNAs potentially involved in circadian rhythm regulation of the retina, we performed miRNA expression profiling with retinal RNA harvested at noon (Zeitgeber time 5) and midnight (Zeitgeber time 17) and identified a subgroup of 12 miRNAs, including members of the miR-183/96/182 cluster with diurnal variation in expression pattern. Our results suggest that miR-96 and miR-182 are involved in circadian rhythm regulation, perhaps by modulating the expression of adenylyl cyclase VI (ADCY6).
                Bookmark

                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                3 April 2009
                12 April 2009
                May 2009
                01 November 2009
                : 41
                : 5
                : 614-618
                Affiliations
                [1 ]Wellcome Trust Sanger Institute, Hinxton, UK
                [2 ]MRC Institute of Hearing Research, Nottingham, UK
                [3 ]GSF National Research Center for Environment and Health, Munich, Germany
                [4 ]School of Biological Sciences, University of East Anglia, Norwich, UK
                [5 ]Unidad de Genética Molecular, Hospital Ramón y Cajal, 28034 Madrid, Spain and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain
                Author notes

                Author contributions. The mutagenesis programme was carried out by H.F. and M.H.D.A. E.Q. analysed the behaviour, the middle and inner ear and the ultrastructural phenotype of the mutant and mapped the mutation. M.L., E.Q. and A.M.G. sequenced the region. Microarrays were run by C.L., and bioinformatic analysis carried out by S.V.D., C.A.G and A.E. Motif analysis was done by M.P. N.R. and T.D. carried out the luciferase assays. Literature searches, in situ hybridisation, immunohistochemistry,, quantitative RT-PCR and data analyses were done by M.L. M.A.M.P. shared data and ideas. K.P.S. conceived and devised the screen for new deaf mutants, obtained the funding, managed the programme, carried out the electrophysiology, and interpreted the data. The paper was written by M.L., E.Q. and K.P.S.

                Author information. The microarray data has been deposited in the ArrayExpress database, accession number E-TABM-489. Correspondence and requests for materials should be addressed to K.P.S. ( kps@ 123456sanger.ac.uk ).

                Article
                UKMS4251
                10.1038/ng.369
                2705913
                19363478
                985ff304-dada-4c55-9735-ce862fa0f3b8
                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 077198 || WT
                Funded by: Wellcome Trust :
                Award ID: 077189 || WT
                Funded by: Medical Research Council :
                Award ID: G0300212 || MRC_
                Categories
                Article

                Genetics
                Genetics

                Comments

                Comment on this article