REVIEW ARTICLE published: 23 December 2013 doi: 10.3389/fnmol.2013.00052 MicroRNAs in sensorineural diseases of the ear Kathy Ushakov, Anya Rudnicki and Karen B. Avraham* Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience,Tel Aviv University,Tel Aviv, Israel Edited by: Hermona Soreq, The Hebrew University of Jerusalem, Israel Reviewed by: Hansen Wang, University ofToronto, Canada Baojin Ding, University of Massachusetts Medical School, USA *Correspondence: Karen B. Avraham, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience,Tel Aviv University, Tel Aviv 69978, Israel e-mail: karena@post.tau.ac.il Non-coding microRNAs (miRNAs) have a fundamental role in gene regulation and expres- sion in almost every multicellular organism. Only discovered in the last decade, miRNAs are already known to play a leading role in many aspects of disease. In the vertebrate inner ear, miRNAs are essential for controlling development and survival of hair cells. Moreover, dysregulation of miRNAs has been implicated in sensorineural hearing impairment, as well as in other ear diseases such as cholesteatomas, vestibular schwannomas, and otitis media. Due to the inaccessibility of the ear in humans, animal models have provided the optimal tools to study miRNA expression and function, in particular mice and zebrafish. A major focus of current research has been to discover the targets of the miRNAs expressed in the inner ear, in order to determine the regulatory pathways of the auditory and vestibular systems. The potential for miRNAs manipulation in development of therapeutic tools for hearing impairment is as yet unexplored, paving the way for future work in the field. Keywords: deafness, inner ear, cochlea, vestibule, microRNAs INTRODUCTION Hearing loss (HL) is the most prominent neurosensory dis- order in humans. Congenital deafness affects at least one in 500 newborns and more than half of these cases are hereditary (National Institutes of Health, NIDCD) 1 . As HL is also age depen- dent, more individuals can be affected at later stages of their lives. The ear is a complex transducing organ, which consists of both exterior and interior parts. Vibrations of the middle ear’s bones mirroring incoming sounds are translated into vibration of the basilar membrane, which in turn leads to mechanotrans- duction at the organ of Corti in specified cells, the hair cells. Mammalian auditory hair cells, surrounded by non-sensory sup- porting cells, are the main functional components of the cochlea. They are organized in three rows of outer hair cells (OHC) and one row of inner hair cells (IHC). Their apical actin-based microvilli are referred to as stereocilia. The mechanical stimu- lus sensed by the stereocilia is converted into an action potential, which in turn transfers the detected sound to the brain (Kelley, 2006). Specifically, coding of sound travels to the higher audi- tory systems via the brainstem, where there are synapses in the cochlear nuclei and the superior olivary complex (SOC), to the inferior colliculus of the midbrain and finally to the auditory cortex. For many years, the conventional dogma in molecular biology defined the mammalian genome as one containing protein-coding genes and other repetitive and non-transcribed sequences. The latter was deemed to be non-essential, unless directly involved in RNA synthesis. The last decade has completely reversed this view and the field of non-coding RNAs (ncRNAs) has undergone a dramatic metamorphosis as a portion of these RNAs, microRNAs (miRNAs) are now recognized as having a vital role in gene expres- sion and function. The first recognized miRNAs were lin-7 and let-7 in Caenorhabditis elegans (Lagos-Quintana et al., 2001), but 1 http://www.nidcd.nih.gov/health/statistics/hearing.html since then the number of these regulatory RNAs has grown to 30,424 mature miRNA sequences in 206 species (Kozomara and Griffiths-Jones, 2011) 2 . miRNAs are the most studied and under- stood forms of ncRNAs, and have been shown to fulfill regulatory functions in many species, including the mammalian system. miRNAs are small ∼23 nucleotide long RNA species. Pri- miRNAs are transcribed together with other forms of RNA by RNA polymerase II and processed through the Drosha–Dicer pathway (Carthew and Sontheimer, 2009). While still in the nucleus, pri- miRNAs are cleaved by Drosha and exported to the cytoplasm via exportin 5. The product of the cleavage pre-miRNA hairpin is composed of the main -5p and the complementary -3p (for- mally star) strands that are connected by the stem loop. In the cytoplasm, the pre-miRNA is cleaved by a second enzyme, Dicer, to produce the mature miRNA. miRNAs possess a seed region of 7 nt that determines its target specificity (Bartel, 2009). Upon sequence complementarity, this region will bind to sequences at the 3 ′ untranslated region (UTR) of target genes. In this fash- ion, miRNAs inhibit target mRNAs by translational repression and mRNA destabilization (Guo et al., 2010) and regulate gene expres- sion through the RNA interference (RNAi) pathway. Another group of ncRNAs, long intervening noncoding RNAs (lincRNAs), while more elusive in their classification, are considered to have expansive roles in gene regulation (Ulitsky and Bartel, 2013). How have ncRNAs contributed to the study of the auditory and vestibular systems? miRNAs were first described in the zebrafish inner ear in 2005 (Wienholds et al., 2005), which heralded a num- ber of studies in the mammalian inner ear worldwide. The study of lincRNAs has not yet advanced at the same pace. miRNAs IN THE INNER EAR Since miRNAs have become an essential and fascinating aspect of gene regulation in the inner ear, hundreds of miRNAs have 2 http://www.mirbase.org Frontiers in Molecular Neuroscience www.frontiersin.org December 2013 | Volume 6 | Article 52 | 1