MicroRNAs in inner ear biology and pathogenesis

doi:10.1016/j.heares.2012.03.008

Hearing Research

Volume 287, Issues 1–2, May 2012, Pages 6-14

https://doi.org/10.1016/j.heares.2012.03.008 Get rights and content

Abstract

MicroRNAs (miRNA) are a group of small noncoding RNAs that regulate gene expression. The discovery of these small RNAs has added a new layer of complexity to molecular biology. Every day, new advances are being made in understanding the biochemistry and genetics of miRNAs and their roles in cellular function and homeostasis. Studies indicate diverse roles for miRNAs in inner ear biology and pathogenesis. This article reviews recent developments in miRNA research in the field of inner ear biology. A brief history of miRNA discovery is discussed, and their genomics and functional roles are described. Advances in the understanding of miRNA involvement in inner ear development in the zebrafish and the mouse are presented. Finally, this review highlights the potential roles of miRNAs in genetic hearing loss, hair cell regeneration, and inner ear pathogenesis resulting from various pathological insults.

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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ReviewMicroRNAs in inner ear biology and pathogenesis

Abstract

Highlights

Section snippets

History of miRNA research

General function of miRNAs

Expression pattern of miRNAs during inner ear development

Target analysis

miRNAs and genetic hearing loss

miRNAs and hair cell regeneration

miRNA expression in the inner ear under stress

Summary

Acknowledgements

Hear Res.

Cell

Toxicol. Appl. Pharmacol.

Neurosci. Lett.

Hear Res.

Neurobiol. Aging

Med. Hypotheses

Curr. Biol.

Mutat. Res.

Cell

Cell

Semin. Cell Dev. Biol.

Cell

Trends Cell Biol.

Cell

Gene Expr. Patterns

Hear Res.

Brain Res.

Dev. Biol.

Dev. Biol.

Hear Res.

Unified translation repression mechanism for microRNAs and upstream AUGs

BMC Genomics

The role of p53 in apoptosis

Discov. Med.

A uniform system for microRNA annotation

RNA

Dicer is essential for mouse development

Nat. Genet.

Principles of microRNA-target recognition

PLoS Biol.

Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs

RNA

TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing

Nature

Sox2 signaling in prosensory domain specification and subsequent hair cell differentiation in the developing cochlea

Proc. Natl. Acad. Sci. U S A

A parsimonious model for gene regulation by miRNAs

Science

Specificity of microRNA target selection in translational repression

Genes Dev.

Artificial tethering of Argonaute proteins for studying their role in translational repression of target mRNAs

Methods Mol. Biol.

Integration of transcriptomics, proteomics, and microRNA analyses reveals novel microRNA regulation of targets in the mammalian inner ear

PLoS One

Principles and effects of microRNA-mediated post-transcriptional gene regulation

Oncogene

GW182 interaction with Argonaute is essential for miRNA-mediated translational repression and mRNA decay

Nat. Struct. Mol. Biol.

The widespread impact of mammalian MicroRNAs on mRNA repression and evolution

Science

Aminoglycoside antibiotics

Audiol. Neurootol.

MicroRNAs and epigenetic regulation in the mammalian inner ear: implications for deafness

Mamm. Genome

MicroRNAs are essential for development and function of inner ear hair cells in vertebrates

Proc. Natl. Acad. Sci. U S A

Gene expression analysis of forskolin treated basilar papillae identifies microRNA181a as a mediator of proliferation

PLoS One

Analysis of microRNA turnover in mammalian cells following Dicer1 ablation

Nucleic Acids Res.

MicroRNAs regulate brain morphogenesis in zebrafish

Science

microRNA target predictions across seven Drosophila species and comparison to mammalian targets

PLoS Comput. Biol.

Novel microRNA candidates and miRNA-mRNA pairs in embryonic stem (ES) cells

PLoS One

Review
MicroRNAs in inner ear biology and pathogenesis