ReviewMicroRNAs in inner ear biology and pathogenesis
Highlights
► MicroRNAs play a critical role in regulating the developmental process of the inner ear. ► MicroRNAs are associated with progressive hearing loss in humans. ► MicroRNAs participate in the regulatory process of hair cell differentiation during regeneration. ► MicroRNAs play a role in regulating cellular responses to inner ear stress.
Section snippets
History of miRNA research
The first miRNA, Lin-4, was discovered in 1993 (Lee et al., 1993) in a study of developmental mutations in Caenorhabditis elegans (C. elegans). Initially, lin-4 was believed to be a protein-coding gene (Chalfie et al., 1981, Sulston and Horvitz, 1981). However, a subsequent investigation revealed that the lin-4 gene encodes a small noncoding RNA, and not a protein (Sulston and Horvitz, 1981).
Evidence linking miRNAs with mRNAs was obtained from the observation that the lin-4 mutant exhibits
General function of miRNAs
Most miRNA genes are transcribed by RNA polymerase II (Isik et al., 2010, Krol et al., 2010, Lee et al., 2004) to produce a primary miRNA transcript, which is subsequently processed by a microprocessor complex consisting of Drosha, (a type-III RNase) and its cofactor DGCR8 (DiGeorge syndrome critical region gene 8) to generate a precursor miRNA (pre-miRNA) (Han et al., 2004, Lee et al., 2003). The pre-miRNA is then transported out of the nucleus to the cytoplasm by exportin-5 and its cofactor
Expression pattern of miRNAs during inner ear development
Investigation of miRNAs in inner ear biology began with a study of miRNA expression in zebrafish during embryonic development (Wienholds et al., 2005). This investigation discovered that miRs-183, -182, -96 and -200a are expressed in developing inner ears. This finding was subsequently confirmed by other investigators (Kapsimali et al., 2007, Li et al., 2010). Robust expression of miR-183 was detected throughout the entire developmental process. Importantly, these studies revealed spatially and
Target analysis
miRNA regulation of cellular function is achieved by controlling the expression of target genes. Therefore, the identification of miRNA targets is an important step toward understanding the role of miRNAs in cellular function and pathogenesis. One research tool for predicting candidate targets for miRNAs is bioinformatic analysis. By combining different bioinformatic software packages, miRNA/mRNA target pairs can be discovered. Different software packages including miRanda, PicTar, TargetScan,
miRNAs and genetic hearing loss
Since the completion of the human genome project, the exploration of the molecular basis of genetic hearing loss has been an area of intensive study (Hilgert et al., 2009, Mahdieh et al., 2010, Yan and Liu, 2008). Thus far, over 100 loci have been mapped for their connection to non-syndromic sensorineural hearing loss (NSHL; Hereditary Hearing Loss Homepage; http://hereditaryhearingloss.org). However, the molecular mechanisms responsible for genetic hearing loss remain unclear. In the past
miRNAs and hair cell regeneration
It is well known that sensory cells in the mammalian cochlea are unable to regenerate once they are lost. However, inner ear tissue in non-mammalian vertebrates, such as birds, reptiles and fish, has the ability to regenerate sensory cells after injury. This leads to the possibility that by studying regenerative mechanisms in lower vertebrate species, we will be able to identify the biological processes responsible for proliferation and differentiation of cells and be able to use this knowledge
miRNA expression in the inner ear under stress
Recent studies have analyzed the expression profiles of miRNAs in the organ of Corti under various pathological conditions, including oxidative insults, ototoxicity and noise-induced cochlear damage (Wang et al., 2010b, Yu et al., 2010). It is widely accepted that oxidative stress generated during various pathological insults can cause hair cell degeneration (Henderson et al., 2006, Jiang et al., 2007, Kovacic and Somanathan, 2008). However, the regulation of this degenerative process is not
Summary
From these studies, it is evident that miRNAs play a functional role in ear biology during development, regeneration and disease. While miRNA research has advanced rapidly, questions and challenges remain. First, only a small group of miRNA families have been identified in the ear, and many more remain to be identified. It is crucial to understand how miRNAs are processed in the inner ear and to identify which factors are responsible for regulation of miRNA transcription. Second, the inner ear
Acknowledgements
The authors thank Dr. Donald Coling for his helpful comments and suggestions. The research was supported by NIDCD1R01 DC010154-01 to BH Hu.
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2019, GeneCitation Excerpt :The miR-183 family is expressed in hair cells, lateral line neuromasts, sensory cells in the eye and nose, the cranial ganglia, and the epiphysis (Li et al., 2010). Similar to zebrafish development, mice exhibit similar patterns of cochlear differentiation during developmental stages (Patel and Hu, 2012). In the cochlea and vestibule specifically, the miR-183 family proves highly relevant to mouse inner-ear development, beginning from the otic vesicle when invaginated from the otic placode (Sacheli et al., 2009; Soukup et al., 2009).
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2016, Experimental GerontologyActivation of miR-34a/SIRT1/p53 signaling contributes to cochlear hair cell apoptosis: Implications for age-related hearing loss
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