Abstract
Mutations in the microRNA Mir96 cause deafness in mice and humans. In the diminuendo mouse, which carries a single base pair change in the seed region of miR-96, the sensory hair cells crucial for hearing fail to develop fully and retain immature characteristics, suggesting that miR-96 is important for coordinating hair cell maturation. Our previous transcriptional analyses show that many genes are misregulated in the diminuendo inner ear and we report here further misregulated genes. We have chosen three complementary approaches to explore potential networks controlled by miR-96 using these transcriptional data. Firstly, we used regulatory interactions manually curated from the literature to construct a regulatory network incorporating our transcriptional data. Secondly, we built a protein-protein interaction network using the InnateDB database. Thirdly, gene set enrichment analysis was used to identify gene sets in which the misregulated genes are enriched. We have identified several candidates for mediating some of the expression changes caused by the diminuendo mutation, including Fos, Myc, Trp53 and Nr3c1, and confirmed our prediction that Fos is downregulated in diminuendo homozygotes. Understanding the pathways regulated by miR-96 could lead to potential therapeutic targets for treating hearing loss due to perturbation of any component of the network.
Highlights
The diminuendo mouse carries a single base-pair change in the seed region of the microRNA gene Mir[96]
Because the diminuendo mutation appears to delay development, we carried out a microarray on the organ of Corti of newborn homozygote diminuendo and wildtype mice to examine the transcriptome at a younger age than our previous P4 analysis
We carried out a Sylamer analysis to examine the direct effects of the mutant microRNA on the transcriptome
Summary
The diminuendo mouse carries a single base-pair change in the seed region of the microRNA gene Mir[96]. Several of the genes downregulated in Dmdo/Dmdo mice at P4, including Ptprq, Gfi[1], Kcna[10] and Slc26a5 (prestin), cause deafness when mutated[7,8,9,10] and some of the unique characteristics of mice null for these genes are replicated in the diminuendo mouse, such as the short outer hair cells of prestin mutants[6,9], and the delay in hair cell stereocilia differentiation seen in Ptprq functional nulls[11] None of these genes can entirely account for the diminuendo phenotype, nor are any of them direct targets of miR-96; rather, the transcriptome-wide effects of the diminuendo mutation suggest it is regulating many genes through multiple pathways. Our results demonstrate the differences between the methods, and identify several genes highlighted as important in more than one analysis, which are candidates for therapeutic intervention
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