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Pascal Escher, Daniel F. Schorderet, Sandra Cottet; Altered Expression of the Transcription Factor Mef2c during Retinal Degeneration in Rpe65 –/– Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(8):5933-5940. doi: https://doi.org/10.1167/iovs.10-6978.
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To investigate the role of the myocyte enhancer factor 2 (Mef2) transcription factor family in retinal diseases, Mef2c expression was assessed during retinal degeneration in the Rpe65 –/– mouse model of Leber's congenital amaurosis (LCA). Mef2c-dependent expression of photoreceptor-specific genes was further addressed.
Expression of Mef2 members was analyzed by oligonucleotide microarray, quantitative PCR (qPCR), and in situ hybridization. Mef2c-dependent transcriptional activity was assayed by luciferase assay in HEK293T cells.
Mef2c was the only Mef2 member markedly downregulated during retinal degeneration in Rpe65 –/– mice. Mef2c mRNA level was decreased by more than 2-fold at 2 and 4 months and by 3.5-fold at 6 months in retinas of Rpe65 –/– mice. Downregulation of Mef2c at the protein level was confirmed in Rpe65 –/– retinas. The decrease in Mef2c mRNA levels in the developing Rpe65 –/– retinas from postnatal day (P) 13 onward was concomitant with the decreased expression of the rod-specific transcription factors Nrl and Nr2e3. Nrl was further shown to drive Mef2c transcriptional activity, supporting a physiological role for Mef2c in the retina. In addition, Mef2c appeared to act as a transcriptional repressor of its own expression and the expression of the retina-specific retinal G-protein coupled receptor (Rgr), rhodopsin, and M-opsin genes.
These findings highlight the early altered regulation of the rod-specific transcriptional network in Rpe65-related disease. They also indicate that Mef2c may act as a novel transcription factor involved in the development and the maintenance of photoreceptor cells.
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