Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase

Bowes, Cathy; Li, Tiansen; Danciger, Michael; Baxter, Leslie C.; Applebury, Meredithe L.; Farber, Débora B.

doi:10.1038/347677a0

Cited by 778 publications

(433 citation statements)

References 19 publications

Supporting

Mentioning

414

Contrasting

Unclassified

Order By: Relevance

“…Animal models of retinal degeneration have provided a better understanding of disease pathogenesis and have led to the development of novel therapeutic strategies (Delyfer et al, 2004). Many of these animal studies stem from genetically distinct mouse strains, such as the rd mouse, which possesses a mutation of rod-specific phosphodiesterase (Bowes et al, 1990;Jimenez et al, 1996). Other studies have focused attention on strain differences and metabolic consequences of light damage on retina during neonatal hyperoxia (Chan et al, 2005;Wu et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

View full text Add to dashboard Cite

This study evaluated the role of crystallins in retinal degeneration induced by chemical hypoxia. Wild type, αA-crystallin (−/−), and αB-crystallin (−/−) mice received intravitreal injection of 12 nmol (low dose), 33 nmol (intermediate dose) or 60 nmol (high dose) cobalt chloride (CoCl 2 ). Hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) stains were performed after 24 hours, 96 hours, and 1 week post-injection, while immunofluorescent stains for αA-and αB-crystallin were performed 1 week post-injection. The in vitro effects of CoCl 2 on αB-crystallin expression in ARPE-19 cells were determined by real time RT-PCR, Western blot, and confocal microscopy and studies evaluating subcellular distribution of αB-crystallin in the mitochondria and cytosol were also performed. Histologic studies revealed progressive retinal degeneration with CoCl 2 injection in wild type mice. Retinas of CoCl 2 injected mice showed transient increased expression of HIF-1α which was maximal 24 hours after injection. Intermediate dose CoCl 2 injection was associated with increased retinal immunofluorescence for both αA-and αB-crystallin; however, after high dose injection, increased retinal degeneration was associated with decreased levels of crystallin expression. Injection of CoCl 2 at either intermediate or high dose in αA-crystallin (−/−) and αB-crystallin (−/−) mice resulted in much more severe retinal degeneration compared to wild type eyes. A decrease in ARPE-19 total and cytosolic αB-crystallin expression with increasing CoCl2 treatment and an increase in mitochondrial αB-crystallin were found. We conclude that lack of α-crystallins accentuates retinal degeneration in chemically-induced hypoxia in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Yaung

Kannan

Wawrousek

et al. 2008

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…Light stimulates phototransduction by activating PDE6AB to hydrolyze a second messenger cGMP and close cGMP-gated channels in the photoreceptor plasma membrane (19,20). Mutations in PDE6AB are known to cause retinal degeneration in humans and animal models by elevating intracellular cGMP concentration and triggering photoreceptor cell death (21)(22)(23)(24)(25). Thus, defective PDE6 function due to mutations in AIPL1 readily explains LCA4.…”

mentioning

confidence: 99%

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Majumder

Gopalakrishna

Cheguru

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Mutations in AIPL1, a chaperone of the lipidated visual effector phosphodiesterase-6, cause severe childhood blindness. Results: AIPL1 binds the farnesyl lipid moiety. The unique insert region of AIPL1 is critical for this interaction. Conclusion: The AIPL1-farnesyl interaction suggests its role in the interaction with phosphodiesterase-6 and normal function of AIPL1. Significance: This study describes a novel mechanism of AIPL1 in retina disease.

show abstract

“…Mutations in the ␤-subunit of cGMP-PDE (␤-PDE) are currently the most common known cause of autosomal recessive retinitis pigmentosa (3). In addition, mutations in the ␤-PDE gene result in congenital stationary night blindness (4) and retinal degeneration in animal models (5)(6)(7)(8). Recently, genetic defects in transcription mechanisms that control the expression of several retina-specific genes have been linked to different types of retinal disorders (9 -12).…”

mentioning

confidence: 99%

Nrl and Sp Nuclear Proteins Mediate Transcription of Rod-specific cGMP-phosphodiesterase β-Subunit Gene

Lerner

Gribanova

et al. 2001

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

cGMP-phosphodiesterase (PDE) is the key effector in rod photoreceptor signal transduction. Mutations in the gene encoding its catalytic ␤-subunit (␤-PDE) cause retinal degenerations leading to blindness. We report that the short ؊93 to ؉53 sequence in the upstream region of this gene is sufficient for ␤-PDE transcription in both Y79 human retinoblastoma cells and Xenopus embryo heads maintained ex vivo. This sequence also functions as a minimal rod-specific promoter in transgenic Xenopus tadpoles. The Nrl transcription factor binds in vitro to the ␤Ap1/NRE regulatory element located within this region and transactivates it when overexpressed in nonretinal 293 embryonic kidney cells. We also found a G/Crich activator element, ␤/GC, important for promoter activity in Y79 retinoblastoma cells and Xenopus embryos. Both the ubiquitous Sp1 and the central nervous system-specific Sp4 transcription factors are expressed in retina and interact with this element in vitro. Electrophoretic mobilities of ␤/GC-Y79 nuclear protein complexes are altered by antibodies against Sp1 and Sp4. Thus, our results implicate Nrl, Sp1, and Sp4 in transcriptional regulation of the rod-specific minimal ␤-PDE promoter. We also conclude that Xenopus laevis is an efficient system for analyzing the human ␤-PDE promoter and may be used to study other human retinal genes ex vivo and in vivo.The vertebrate retina is a highly specialized sensory extension of the central nervous system responsible for light perception and conversion into a neural stimulus, phototransduction as well as the initial visual signal integration and processing. Phototransduction occurs both in rod and cone photoreceptors. During rod phototransduction, rhodopsin-activated transducin activates cGMP-phosphodiesterase (PDE), 1 which leads to the hydrolysis of cGMP and closure of the cGMP-gated transmembrane cationic channels causing hyperpolarization of the plasma membrane and photoreceptor signaling (1).The rod photoreceptor-specific cGMP-PDE is a membraneassociated heterotetrameric enzyme composed of two catalytic ␣-and ␤-subunits and two inhibitory ␥-subunits (2). Each of these subunits is essential for normal cGMP-PDE activity required for phototransduction and the maintenance of retinal health. Mutations in the ␤-subunit of cGMP-PDE (␤-PDE) are currently the most common known cause of autosomal recessive retinitis pigmentosa (3). In addition, mutations in the ␤-PDE gene result in congenital stationary night blindness (4) and retinal degeneration in animal models (5-8). Recently, genetic defects in transcription mechanisms that control the expression of several retina-specific genes have been linked to different types of retinal disorders (9 -12). Thus, it became important to elucidate the molecular events that regulate transcription of the ␤-PDE gene, because abnormalities in these control mechanisms may be detrimental for photoreceptor function and structural integrity.The objective of this investigation was to determine the cis-acting elements and the trans-acting nucle...

show abstract

Retinal degeneration in the rd mouse is caused by a defect in the β subunit of rod cGMP-phosphodiesterase

Cited by 778 publications

References 19 publications

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia

Interaction of Aryl Hydrocarbon Receptor-interacting Protein-like 1 with the Farnesyl Moiety

Nrl and Sp Nuclear Proteins Mediate Transcription of Rod-specific cGMP-phosphodiesterase β-Subunit Gene

Contact Info

Product

Resources

About