title: Altered expression of the transcription factor Mef2c during retinal degeneration in Rpe65-/- mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute for Research in Ophthalmology, Sion, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Escher
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Schorderet
authors.forename: Sandra
authors.initials: S
authors.lastname: Cottet
mesh_terms: D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics*; D015870:Gene Expression / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000503:physiopathology; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000503:physiopathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D005136:Eye Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C578041:Mef2c protein, mouse; C485736:Nr2e3 protein, mouse; C084884:Nrl protein, mouse