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Shunbin Xu, Stephen Lumayag, Carolin Haldin, Collen Cowan, Beatrix Kovacs; The miR-183/96/182 Cluster Is Essential For Normal Functions Of The Retina And Other Sensory Organs. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6564.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we identified a highly conserved, paralogous miRNA cluster, the miR-183/96/182 cluster (the miR-183C in short), which includes miR-183, miR-96 and miR-182 in the sequence of transcription. It is highly, specifically expressed in the retina and all sensory organs. The purpose of current study is to uncover in vivo functions of this cluster in the retina.
Using a gene-trap embryonic stem cell clone, we generated a mouse model, designated as the miR-183CGT/GT mice, in which the entire cluster is inactivated. Comprehensive characterization was performed by Northern blot, quantitative RT-PCR, X-gal staining, H&E staining, immunofluorescence electron microscopy, scotopic and photopic electroretinograms (ERGs). Mouse Genome 430A_2 Array (Affymatrix) and custom-made Taqman qRT-PCR microarrays (Applied Biosystem) were used to identify and confirm differentially expressed genes in the retina of miR-183CGT/GT mice compared to their wild type littermates. Light damage experiment was performed by exposing dark-adapted animals to 10,000 lux light for 2 hours, followed by 2 weeks in the dark.
1. The miR-183C is inactivated in the retina and all other sensory organs of miR-183CGT/GT mice.2. Expression of the β-geo cassette followed native expression patterns of thecluster in the retina and other sensory organs.3. Functionally, miR-183CGT/GT mice showed progressive defects in both scotopic and photopic ERGs, starting as early as 5 weeks old, suggesting that both rod and cone photoreceptors are affected.4. miR-183CGT/GT mice showed slowly-progressing retinal degeneration, and increased susceptibility to light damage.5. Inactivation of the miR-183C resulted in global gene-expression changes in the retina, with significant enrichment of genes important for photoreceptor cell-fate and subtype determination, phototransduction, visual cycles, cellular proliferation and survival, synaptogenesis and neural transmission.6. In addition, the miR-183CGT/GT mice demonstrate signs of obvious defects in vestibular function, suggesting dysfunctions in other sensory systems.
1. The miR-183C is required for normal retinal terminal differentiation and maturation, and normal functions of the retina. To our knowledge, this is the first animal model of retinal degeneration caused by inactivation of an individual miRNA gene.2. The miR-183C gene is a candidate gene for inherited retinal degenerative diseases, and may contribute to sporadic age-related retinal degenerative diseases.3. The miR-183CGT mouse model provides a unique animal model for in vivo functional studies and expression analysis of the miR-183C in the retina and other sensory organs.
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