CRX
Cone-rod homeobox protein [CORD2]
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Rod and cone photoreceptor neurons in the mammalian retina possess specialized cellular architecture and functional features for converting light to a neuronal signal. Establishing and maintaining these characteristics requires appropriate expression of a specific set of genes, which is tightly regulated by a network of photoreceptor transcription factors centered on the cone-rod homeobox protein CRX. CRX recruits transcription coactivators p300 and CBP to acetylate promoter-bound histones and activate transcription of target genes. To further elucidate the role of these two coactivators, we conditionally knocked out Ep300 and/or CrebBP in differentiating rods or cones, using opsin-driven Cre recombinase. Knockout of either factor alone exerted minimal effects, but loss of both factors severely disrupted target cell morphology and function: the unique nuclear chromatin organization seen in mouse rods was reversed, accompanied by redistribution of nuclear territories associated with repressive and active histone marks. Transcription of many genes including CRX targets was severely impaired, correlating with reduced histone H3/H4 acetylation (the products of p300/CBP) on target gene promoters. Interestingly, the presence of a single wild-type allele of either coactivator prevented many of these defects, with Ep300 more effective than Cbp. These results suggest that p300 and CBP play essential roles in maintaining photoreceptor-specific structure, function and gene expression.
MeSH Terms
- Acetylation
- Aging
- Animals
- Chromatin
- E1A-Associated p300 Protein
- Gene Expression Regulation
- Heterozygote
- Histones
- Membrane Proteins
- Mice
- Mice, Knockout
- Phenotype
- Phosphoproteins
- Promoter Regions, Genetic
- Retinal Cone Photoreceptor Cells
- Retinal Rod Photoreceptor Cells
- Trans-Activators
- Transcription, Genetic
The review considers the molecular-cellular mechanisms of retina pathology in people of various age. Dysfunction of retinal cells (retinal pigment epithelium, photoreceptors, neurons) causes the development of age-related macular degeneration, retinal ischemia and a variety of hereditary diseases. This is the description of involvement of genes and signaling molecules in the dysfunction of retinal cell types. It is established that a breach of RPE65 gene expression leads to age-related macular degeneration, retinitis pigmentosa and Leber's congenital amaurosis. Mutations in the CRX gene are the cause of progressive states such as cone-rod dystrophy. In addition, more than 100 mutations in RHO have been identified, leading to different variants of retinitis pigmentosa. The involvement of TGF-(beta2 in the formation of retinal cells and the regulation of secretion of vascular endothelial growth factor VEGF, which synthesis is increased by ischemic lesions of the retina, is described.
MeSH Terms
- Aging
- Eye Proteins
- Gene Expression Regulation
- Genetic Predisposition to Disease
- Humans
- Mutation
- Retina
- Retinal Diseases
- Retinal Neurons
- Retinal Pigments
Increased oxidative stress is known to accelerate age-related pathologies. Beta-cryptoxanthin (β-CRX, (3R)-β,β-caroten-3-ol) is a potent antioxidant that is highly rich in Satsuma mandarin orange (mandarin), which is the most popular fruit in Japan. We investigated the antioxidative and anti-aging effects of β-CRX and mandarin using senescence-accelerated mice (SAMP10), which were characterized by a short lifespan, high generation of superoxide anions in the brain and poor learning ability with aging. β-CRX (0.5-5.0 µg/ml) or mandarin juice (3.8-38.0%) was added to drinking water of SAMP10 one to 12 months of age. β-CRX was dose-dependently incorporated into the cerebral cortex and the contents were similar to the concentration of β-CRX in the human frontal lobe. These mice also had higher learning ability. The level of DNA oxidative damage was significantly lower in the cerebral cortex of mice that ingested β-CRX and mandarin than control mice. In addition, the mice that ingested β-CRX (>1.5 µg/ml) and mandarin (>11.3%) exhibited a higher survival when 12 month-old, the presenile age of SAMP10, than control mice. These results suggest that β-CRX is incorporated into the brain and has an important antioxidative role and anti-aging effect.
MeSH Terms
- Aging
- Animals
- Antioxidants
- Brain
- Citrus
- Cognition Disorders
- Cryptoxanthins
- DNA Damage
- Dose-Response Relationship, Drug
- Fruit
- Learning
- Longevity
- Male
- Mice
- Mice, Inbred Strains
- Oxidative Stress
- Phytotherapy
- Plant Preparations
- Xanthophylls
In this study, we compared the temporal expression pattern of four retinal genes; rho1 and rho2 that encode subunits of GABA(c) receptors, L7 that encodes Purkinje cell protein and CRX that encodes the cone-rod homeobox transcription factor. A reverse-transcription-polymerase chain reaction (RT-PCR) strategy that generated a linear correlation between the amount of retinal RNA and the amount of amplified product was used to quantify transcripts from each gene. Results with this method showed that the rho1 and L7 have similar developmental patterns. Both exhibit basal level expression before P7. From P7 to P20, the RNA levels for both genes were increased about 12-fold. After P20, the RNA levels remained unchanged. Compared to rho1 and L7, expression of rho2 began later, since the rho2 RNA could not be detected until P10. At P10, the rho2 RNA level was about 10% of its level at P35. Expression of rho2 reached its peak at a later developmental stage compared to that of rho1 and L7. The different temporal patterns were confirmed by co-amplification of rho1, rho2, and L7 in a single PCR tube. CRX RNA was detected at embryonic day 15 (E15) and increased progressively, in agreement with a prior study using in situ hybridization. These data, combined with evidence that the tissue distribution of rho1 and L7 RNA in the CNS are similar, indicates that rho1 and L7 may share common transcriptional regulatory elements. Furthermore, the difference in the timing of rho subunit expression suggests that the subunit composition of GABA(c) receptors vary during retinal development.
MeSH Terms
- Aging
- Animals
- Animals, Newborn
- Fetus
- Gene Expression Regulation, Developmental
- Homeodomain Proteins
- Mice
- Mice, Inbred C57BL
- Nerve Tissue Proteins
- RNA, Messenger
- Receptors, GABA
- Receptors, GABA-A
- Receptors, GABA-B
- Retina
- Reverse Transcriptase Polymerase Chain Reaction
- Trans-Activators
- Transcription, Genetic