PMC:3886832 / 18624-22785 JSONTXT

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Gene Expression Following Inner Ear Trauma\nA number of microarray studies have examined gene expression following trauma to the non-regenerative mammalian cochlea. These and other inner ear microarray studies are more thoroughly reviewed by Hertzano and Elkon [29]. Gene expression in mammalian (non-regenerative) models can be compared to shifts in gene expression patterns following trauma to the non-mammalian (regenerative) inner ear to highlight functional pathways involved in hair cell death and regeneration. Although the process of regeneration of adult inner ear tissue may recapitulate some of the same processes of initial sensory epithelial development, it is highly likely that there are important differences, as well. Thus, measuring gene expression in tissues that are going through the regeneration process is the most direct way to discover what pathways are activated during hair cell regeneration. \nTrauma to the ear can be produced by ototoxic chemicals [24], acoustic overstimulation [25,44,65] or laser ablation [24]. Hawkins et al. [24] performed the first large-scale microarray experiment on regenerating auditory tissues. They examined gene expression of TF in cultured avian utricles and cochleae following trauma induced by either a pulsed laser microbeam or the ototoxic antibiotic, neomycin. Although there were differences in expression patterns between tissue types and treatments, there were a number of identical gene expression patterns found across treatments during the process of regeneration. Some of the identified signaling pathways were TGFβ, PAX, NOTCH, WNT, NFKappaB, INSULIN/IGF1 and AP1. In addition, p27KIP and genes that regulate its expression and other apoptotic and cell cycle control pathways, were significantly regulated during regenerative proliferation.\nFollowing noise exposure, Schuck et al. [25] examined microarray gene expression patterns in zebrafish ears at two and four days post-exposure. Transcripts that showed the greatest regulation on day 2 compared to control tissues included growth hormone 1 (gh1, upregulated) and major histocompatibility complex, class I, ZE (mhc1ze, downregulated). Many genes that were upregulated on day 2 were downregulated at day 4 and vice versa. Follow-up experiments showed that growth hormone (GH) injection following acoustic exposure led to an increase in cell proliferation and a decrease in apoptosis in the zebrafish inner ear [65]. Insulin-like growth factor 1 (IGF-1) is secreted mainly by the liver and is stimulated by GH. It is required for normal post-natal survival, maturation and differentiation of cochlear ganglion and hair cells [66]. Thus, it is likely that the effects of GH on the zebrafish inner ear are also mediated by IGF-1. A number of genes involved with immune function, including MHC class I and II molecules, were also significantly regulated in the zebrafish ear post-acoustic exposure. These genes may play a role in cell proliferation following hair cell death. When MHC Class I molecules are bound by antibodies, it prevents them from presenting antigens and promotes cell proliferation [67]. Thus, the downregulation of mhc1ze may have promoted increased cell division, as it coincides with a peak in cell proliferation in the zebrafish ear following acoustic trauma [9].\nLiang et al. [44] also examined gene expression in the zebrafish ear after noise exposure, but at more time points (immediately after two days of exposure and one, two and four days post-exposure). They used digital gene expression (DGE), which utilizes tag sequence profiling. Immediately after noise exposure, stat3 and socs3a were significantly upregulated and the stat3/socs3a pathway was the dominant signaling pathway that was regulated. Genes related to this pathway were also significantly regulated (e.g., socs3b, jak1, mmp9). Interestingly, the same or similar genes were found regulated in the zebrafish ear by Schuck et al. [25]. These included socs3b, socs1, mmp13 and stat1b. The stat/socs pathways are activated by GH [68], so it makes sense that these genes are regulated as GH is upregulated following acoustic trauma to the ear.\n"}