Abstract
Purpose: :
Cone degeneration is the hallmark of the inherited retinal disease retinitis pigmentosa. We have previously identified a trophic factor "Rod-derived ConeViability Factor (RdCVF) that is secreted by rods and promote cone viability in mouse model of the disease.
Methods: :
We used a bioinformatic approach to identify , a second trophic factor belonging to the Rod-derived Cone Viability Factor family, RdCVF2.We analysed the phenotype of RdCVF2 knockout mice. The visual function of the RdCVF2 -/- mice has been tested by electroretinography. Next, we tested for possible cone loss in the RdCVF2 -/- mice at two and ten months of age. The animals were sacrificed and the retinas of RdCVF2 -/- mice and their isogenic controls were dissected and labelled with peanut hemaglutinin (PNA) a lectin binding specifically to the matrix sheet surrounding cones. PNA was revealed using an anti-PNA coupled to rhodamine The retinas were flat-mounted and processed for automated image acquisition and cell counting on our platform.
Results: :
We report the bioinformatic identification and the experimental analysis of RdCVF2, a second trophic factor belonging to the Rod-derived Cone Viability Factor family. The mouse RdCVF gene is known to be bifunctional, encoding both a long thioredoxin-like isoform (RdCVF-L) and a short isoform with trophic cone photoreceptor viability activity (RdCVF-S). RdCVF2 shares many similarities with RdCVF in terms of gene structure, expression in a rod-dependent manner. Furthermore, like RdCVF, the RdCVF2 short isoform exhibits cone rescue activity.Next, we Characterized RdCVF2-/- phenotype. The postnatal development of retinal photoreceptors in the RdCVF2-/- mice was indistinguishable from that of wildt type controls as judged by histology and electroretinograms (ERGs) in younger mice. By 10 months of age, 30% of cones were lost. Along with the loss of cones, ERG amplitudes declined so that by 10 months the a- and b-waves were reduced by >60% compared with those of age-matched wild type controls.
Conclusions: :
Taken together, these findings define a new family of bifunctional genes which are expressed in vertebrate retina, encode trophic cone viability factors, and have major therapeutic potential for human retinal neurodegenerative diseases such as retinitis pigmentosa.
Keywords: photoreceptors • retinal degenerations: cell biology • cell survival