Disease relevance of Pde6b

• CONCLUSIONS: The slowing of degeneration in the rd/rd and Q344ter mutant mice demonstrated that intraocularly injected survival factors can protect photoreceptors from degenerating in animal models with the same or similar genetic defects as those in human inherited retinal degenerations [1].
• The rd1 mouse is a relevant model for studying the mechanisms of photoreceptor degeneration in retinitis pigmentosa [2].
• In the inherited degenerative retinal disease of the rd mouse, rod cGMP levels rise above normal due to depressed cGMP-phosphodiesterase (cGMP-PDE) function a few days before degeneration begins [3].
• The provirus is present in every strain of rd mouse tested [4].
• HIV vectors containing a gene encoding a hemagglutinin (HA)-tagged PDEbeta were injected into the subretinal spaces of newborn rd mouse eyes [5].

Psychiatry related information on Pde6b

• Because rd gene induces different age-related degeneration of cones and rods, we have examined age-related changes in the sensitivity to a light pulse for phase-shifting the locomotor activity rhythms in CBA/J-rd/rd mice [6].

High impact information on Pde6b

• We have recently isolated a candidate complementary DNA for the rd gene from a mouse retinal library and completed the characterization of cDNAs encoding all subunits of bovine photoreceptor phosphodiesterase [7].
• Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase [7].
• We conclude that the mouse rd locus encodes the rod photoreceptor cGMP-phosphodiesterase beta subunit [7].
• A new study shows that autologous bone marrow-derived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in two murine models of retinitis pigmentosa, rd1 and rd10, prevent cone loss [8].
• Apoptosis: final common pathway of photoreceptor death in rd, rds, and rhodopsin mutant mice [9].

Chemical compound and disease context of Pde6b

• RESULTS: By every measure, TUDCA greatly slowed retinal degeneration in LIRD and rd10 mice [10].
• These results suggest that photoreceptor degeneration in the rd/rd mouse is a process starting with Ca(2+) toxicity followed by secondary insults involving multidestructive pathways such as apoptosis and neuroinflammation, presumably boosting morphological changes [11].
• In the inherited retinal degeneration of rd mice, cyclic GMP accumulates in affected rod photoreceptors prior to their degeneration [12].
• To study the rescue effect of antioxidants on retinal degeneration, rd1 retinas were studied in vitro and in vivo using lutein, zeaxanthin, alpha lipoic acid and reduced l-glutathione [13].

Biological context of Pde6b

• RESULTS: Point mutations in the seven new alleles of Pde6b were identified: Three generated premature stop codons, two were missense mutations, and two were splice mutations [14].
• Photoreceptor cell death in mice expressing one of the bcl transgenes and carrying either the rd mutation homozygously or the rhodopsin mutation heterozygously was examined by histologic and electroretinographic measurements [15].
• Apoptosis-related nuclear DNA fragmentation, as assessed by in situ labeling with terminal deoxynucleotidyl transferase, was present in 13-day-old rd/rd mouse retinas with or without transgene expression [15].
• We have utilized backcross analysis in mice to verify and define more precisely the location of the Pdeb locus 6.1 +/- 2.3 cM distal of Mgsa on mouse chromosome 5 [16].
• Linkage of the mouse Pdeb locus with other homologues in the human 4p16.3 region is maintained but gene order is not, suggesting at least three possible sites for the corresponding mouse HD gene [16].

Anatomical context of Pde6b

• The rd mouse retina is an animal model for human retinal dystrophy in which the rod photoreceptors undergo apoptosis during the first 4 weeks in vivo or in organ culture [17].
• To provide a more complete understanding of these receptors in vivo, we have utilized a mouse that lacks rod and cone photoreceptors (rd/rd cl) and compared these animals to congenic wild-types [18].
• Aged (approximately 700 days) rd/rd cl mice lose most of their inner retina but retain the retinal ganglion cell layer [18].
• Photoreceptor-specific protein expression of mouse retina in organ culture and retardation of rd degeneration in vitro by a combination of basic fibroblast and nerve growth factors [19].
• At the molecular level, the light induction of c-fos transcription in the suprachiasmatic nucleus was markedly reduced in the triple mutant mouse compared with either rd/rd or cryptochrome mutant mice [20].

Associations of Pde6b with chemical compounds

• METHODS: Retinal morphometry was performed at the light microscopic level in caspase-3 mutant mice from PN0 through PN23, and in rd-1/caspase-3 double mutant mice at PN14, -16, and -18 [21].
• To genetically define the roles of these pigments in light modulation of behavior, we generated rd/rd;mCry1(-)/mCry1(-);mCry2(-)/mCry2(-) mutant mice lacking rods and most cones as well as both cryptochrome proteins [20].
• To examine this hypothesis further, a murine photoreceptor-derived cell line (661W) was treated with the Ca(2+) ionophore A23187, cGMP-gated channel agonist 8-bromo-cGMP, or phosphodiesterase inhibitor isobutylmethylxanthine to mimic the increased Ca(2+) influx seen in the rd photoreceptors [22].
• It is suggested that in the rd mouse the absence of photoreceptors, perhaps coupled with lack of normal interphotoreceptor matrix, leads to a loss in the ability of the pigment epithelium to store retinyl esters [23].
• Using microarray techniques, transcript levels of cyclic AMP response element-binding protein (CREB)-1, calpastatin and of various calpain genes were analysed in the rd1 mouse compared with its wild-type control [24].

Regulatory relationships of Pde6b

• Synthesis and secretion of IRBP in vitro was less than 10% of the controls in rd retinas at P26, when only 4-5% of the photoreceptors survived [23].
• Adenovirus-mediated delivery of rhodopsin-promoted bcl-2 results in a delay in photoreceptor cell death in the rd/rd mouse [25].
• Calpain is activated in degenerating photoreceptors in the rd1 mouse [24].
• Glial cell line-derived neurotrophic factor induces histologic and functional protection of rod photoreceptors in the rd/rd mouse [26].
• We found that Fos is expressed in the rd retina in an unattenuated pattern through the entire life of the animal [27].

Other interactions of Pde6b

• PURPOSE: The primary purpose of this study was to evaluate the impact of caspase-3 ablation on photoreceptor degeneration in the rd-1 mouse [21].
• Since the rd gene is located on mouse chromosome 5, our results suggest that Sag is not the site of the rd mutation [28].
• Genotyping confirmed the presence of a viral insertion of rd1 gene in the mocha strain [29].
• Since the locus of the rd mutation is on mouse chromosome 5, a defect in the Pdea gene is ruled out as the cause of this inherited retinal degeneration [3].
• In a recent study, we reported that bFGF content and mRNA expression levels are elevated in degenerating photoreceptors in the rd mouse retina as compared to the levels in photoreceptors in age matched normal retinas (Gao and Hollyfield, 1995) [30].

Analytical, diagnostic and therapeutic context of Pde6b

• METHODS: Conformation sensitive capillary electrophoresis and DNA sequencing were used to identify the mutations in the Pde6b gene [14].
• Growth factors in combination, but not individually, rescue rd mouse photoreceptors in organ culture [17].
• A polymerase chain reaction assay revealed that all of the NIH Swiss and Black Swiss mice tested were homozygous for the recessive retinal degeneration 1 mutation of the Pde6b gene [31].
• In this study, genomic DNA mapping and sequence analyses clarify the position of the proviral sequences in relation to the rd gene [4].
• On Northern blots the candidate rd cDNA hybridizes a 3.3-kilobase RNA species from 9- to 11-day-old developing normal retina and, much more faintly, a 3.6-kb RNA species from age-matched rd retina [32].

References