The homeobox gene CHX10/VSX2 regulates RdCVF promoter activity in the inner retina.
Rod-derived Cone Viability Factor (RdCVF) is a trophic factor with therapeutic potential for the treatment of retinitis pigmentosa, a retinal disease that commonly results in blindness. RdCVF is encoded by Nucleoredoxin-like 1 (Nxnl1), a gene homologous with the family of thioredoxins that participate in the defense against oxidative stress. RdCVF expression is lost after rod degeneration in the first phase of retinitis pigmentosa, and this loss has been implicated in the more clinically significant secondary cone degeneration that often occurs. Here, we describe a study of the Nxnl1 promoter using an approach that combines promoter and transcriptomic analysis. By transfection of selected candidate transcription factors, chosen based upon their expression pattern, we identified the homeodomain proteins CHX10/VSX2, VSX1 and PAX4, as well as the zinc finger protein SP3, as factors that can stimulate both the mouse and human Nxnl1 promoter. In addition, CHX10/VSX2 binds to the Nxnl1 promoter in vivo. Since CHX10/VSX2 is expressed predominantly in the inner retina, this finding motivated us to demonstrate that RdCVF is expressed in the inner as well as the outer retina. Interestingly, the loss of rods in the rd1 mouse, a model of retinitis pigmentosa, is associated with decreased expression of RdCVF by inner retinal cells as well as by rods. Based upon these results, we propose an alternative therapeutic strategy aimed at recapitulating RdCVF expression in the inner retina, where cell loss is not significant, to prevent secondary cone death and central vision loss in patients suffering from retinitis pigmentosa.
Department of Genetics, Institut de la Vision, INSERM Université Pierre et Marie Curie-Paris 6, UMR-S 968, Paris, France.
Sacha
S
Reichman
Ravi Kiran Reddy
RK
Kalathur
Sophie
S
Lambard
Najate
N
Aït-Ali
Yanjiang
Y
Yang
Aurélie
A
Lardenois
Raymond
R
Ripp
Olivier
O
Poch
Donald J
DJ
Zack
José-Alain
JA
Sahel
Thierry
T
Léveillard
D000818:Animals; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012160:Retina / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D005136:Eye Proteins; D018398:Homeodomain Proteins; C488098:NXNL1 protein, human; C525119:RdCVF protein, mouse; D014157:Transcription Factors; C490289:VSX2 protein, human; C088975:Vsx2 protein, mouse; D013879:Thioredoxins