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      Sensory hair cell death and regeneration in fishes

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          Abstract

          Sensory hair cells are specialized mechanotransductive receptors required for hearing and vestibular function. Loss of hair cells in humans and other mammals is permanent and causes reduced hearing and balance. In the early 1980’s, it was shown that hair cells continue to be added to the inner ear sensory epithelia in cartilaginous and bony fishes. Soon thereafter, hair cell regeneration was documented in the chick cochlea following acoustic trauma. Since then, research using chick and other avian models has led to great insights into hair cell death and regeneration. However, with the rise of the zebrafish as a model organism for studying disease and developmental processes, there has been an increased interest in studying sensory hair cell death and regeneration in its lateral line and inner ears. Advances derived from studies in zebrafish and other fish species include understanding the effect of ototoxins on hair cells and finding otoprotectants to mitigate ototoxin damage, the role of cellular proliferation vs. direct transdifferentiation during hair cell regeneration, and elucidating cellular pathways involved in the regeneration process. This review will summarize research on hair cell death and regeneration using fish models, indicate the potential strengths and weaknesses of these models, and discuss several emerging areas of future studies.

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          Most cited references 199

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          A genetic screen for mutations affecting embryogenesis in zebrafish.

          Systematic genome-wide mutagenesis screens for embryonic phenotypes have been instrumental in the understanding of invertebrate and plant development. Here, we report the results from the first application of such a large-scale genetic screening to vertebrate development. Male zebrafish were mutagenized with N-ethyl N-nitrosourea to induce mutations in spermatogonial cells at an average specific locus rate of one in 651 mutagenized genomes. Mutations were transmitted to the F1 generation, and 2205 F2 families were raised. F3 embryos from sibling crosses within the F2 families were screened for developmental abnormalities. A total of 2337 mutagenized genomes were analyzed, and 2383 mutations resulting in abnormal embryonic and early larval phenotypes were identified. The phenotypes of 695 mutants indicated involvement of the identified loci in specific aspects of embryogenesis. These mutations were maintained for further characterization and were classified into categories according to their phenotypes. The analyses and genetic complementation of mutations from several categories are reported in separate manuscripts. Mutations affecting pigmentation, motility, muscle and body shape have not been extensively analyzed and are listed here. A total of 331 mutations were tested for allelism within their respective categories. This defined 220 genetic loci with on average 1.5 alleles per locus. For about two-thirds of all loci only one allele was isolated. Therefore it is not possible to give a reliable estimate on the degree of saturation reached in our screen; however, the number of genes that can mutate to visible embryonic and early larval phenotypes in zebrafish is expected to be several-fold larger than the one for which we have observed mutant alleles during the screen. This screen demonstrates that mutations affecting a variety of developmental processes can be efficiently recovered from zebrafish.
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            Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals.

            In the mammalian auditory system, sensory cell loss resulting from aging, ototoxic drugs, infections, overstimulation and other causes is irreversible and leads to permanent sensorineural hearing loss. To restore hearing, it is necessary to generate new functional hair cells. One potential way to regenerate hair cells is to induce a phenotypic transdifferentiation of nonsensory cells that remain in the deaf cochlea. Here we report that Atoh1, a gene also known as Math1 encoding a basic helix-loop-helix transcription factor and key regulator of hair cell development, induces regeneration of hair cells and substantially improves hearing thresholds in the mature deaf inner ear after delivery to nonsensory cells through adenovectors. This is the first demonstration of cellular and functional repair in the organ of Corti of a mature deaf mammal. The data suggest a new therapeutic approach based on expressing crucial developmental genes for cellular and functional restoration in the damaged auditory epithelium and other sensory systems.
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              Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears.

              For mammalian cochlear hair cells, fate determination is normally completed by birth. We report here that overexpression of Math1, a mouse homolog of the Drosophila gene atonal, in postnatal rat cochlear explant cultures resulted in extra hair cells. Surprisingly, we found that the source of the ectopic hair cells was columnar epithelial cells located outside the sensory epithelium in the greater epithelial ridge, which normally give rise to inner sulcus cells. Moreover, Math1 expression also facilitated conversion of postnatal utricular supporting cells into hair cells. Thus Math1 was sufficient for the production of hair cells in the ear, and immature postnatal mammalian inner ears retained the competence to generate new hair cells.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                21 April 2015
                2015
                : 9
                Affiliations
                1Department of Biology, Western Kentucky University Bowling Green, KY, USA
                2Department of Genetics and Genome Sciences, University of Connecticut Health Center Farmington, CT, USA
                Author notes

                Edited by: Francesco Moccia, University of Pavia, Italy

                Reviewed by: Hernan Lopez-Schier, Helmholtz Zentrum Munchen, Germany; Jonathan I. Matsui, Harvard University, USA

                *Correspondence: Michael E. Smith, Department of Biology, Western Kentucky University, 1906 College Heights Blvd., Bowling Green, KY 42101, USA michael.smith1@ 123456wku.edu
                Article
                10.3389/fncel.2015.00131
                4404912
                Copyright © 2015 Monroe, Rajadinakaran and Smith.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 5, Tables: 1, Equations: 0, References: 215, Pages: 18, Words: 16503
                Categories
                Neuroscience
                Review

                Neurosciences

                lateral line, acoustic trauma, teleost, cell death, zebrafish, ototoxicity, regeneration, hair cell

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