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Lulu Yan, Olivia Szereszowiec, Brahim Chaqour; Regulating the Regulator: MicroRNA-dependent Control of the Pro-angiogenic Activity of the Matricellular Protein CCN1 in Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5579.
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Normal and pathological angiogenesis are associated with the coordinated or aberrant expression of stimulatory and inhibitory angiogenesis regulatory factors. The CCN1 protein also known as Cysteine-rich protein 61, an extracellular matrix-associated integrin-binding signaling molecule, regulates endothelial cell differentiation, growth, migration and angiogenesis during development and tissue repair. Expression of the CCN1 gene depends on both transcriptional and post-transcriptional events. MicroRNAs (miRNAs) are ubiquitously expressed short, non-coding RNAs that play key roles in the regulation of angiogenic gene expression and cellular function. This study examined the expression pattern of the CCN1 gene and the potential role of miRNAs in its regulation in the retina under normal and ischemic conditions.
Expression and tissue localization of the CCN1 protein in the retina was determined by immunohistochemical methods in transgenic mice expressing a green fluorescent protein (GFP) reporter under the control of the CCN1 promoter and in wild-type mice upon induction of oxygen-induced retinopathy (OIR) (exposure of mouse pups to 75% oxygen for 5 days at postnatal day 7 followed by normoxia for 5 days). MicroRNAs targeting the CCN1 gene were identified by miRNA target prediction software and real time PCR quantification of the identified miRNAs in OIR retinas under hyperoxic and ischemic conditions.
CCN1 was transiently expressed in the retinal vasculature as the superficial capillary plexus forms and dives deeper in the retinal layers. However, CCN1 mRNA and protein levels became abnormally repressed during the hyperoxic and ischemic phases of OIR. We identified several miRNAs that putatively target the CCN1 gene’s 3’ untranslated region (UTR). Five of these (miR-155, miR-181a, miR-221, miR-222, miR-22) are highly conserved across species, suggesting their evolutionary and functional importance. Interestingly, the expression of miR-181a was inversely correlated to that of the CCN1 gene under ischemic conditions, suggesting a regulatory relationship between miR-181 and the CCN1 gene.
Suppressed expression of the CCN1 gene in ischemic retinopathy modeled in OIR mice is correlated to dysregulated expression of specific miRNAs in the retina.
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