Defective Phagocytosis of Isolated Rod Outer Segments by RCS Rat Retinal Pigment Epithelium in Culture

Edwards, Ross B.; Szamier, R. Bruce

doi:10.1126/science.560718

Cited by 226 publications

(122 citation statements)

References 13 publications

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“…In addition, photoreceptors transfer toxic metabolites to RPE cells, which are responsible for their elimination through metabolic conversion or delivery to the blood. RPE cells are also involved in the phagocytic elimination of dead or damaged photoreceptors (Young and Bok 1969;Edwards and Szamier 1977;Bok 1993). However, less is known about protective programs that are intrinsic to RPE cells, despite the fact that defects in these cells are major causes of retinal degenerative diseases such as AMD (Hamdi and Kenney 2003;Zarbin 2004;Sparrow and Boulton 2005).…”

Section: Discussionmentioning

confidence: 99%

Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

Kim¹,

Kang²,

Burrola³

et al. 2008

Genes Dev.

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Adhesion between epithelial cells mediates apical-basal polarization, cell proliferation, and survival, and defects in adhesion junctions are associated with abnormalities from degeneration to cancer. We found that the maintenance of specialized adhesions between cells of the retinal pigment epithelium (RPE) requires the phosphatase PTEN. RPE-specific deletion of the mouse pten gene results in RPE cells that fail to maintain basolateral adhesions, undergo an epithelial-to-mesenchymal transition (EMT), and subsequently migrate out of the retina entirely. These events in turn lead to the progressive death of photoreceptors. The C-terminal PSD-95/Dlg/ZO-1 (PDZ)-binding domain of PTEN is essential for the maintenance of RPE cell junctional integrity. Inactivation of PTEN, and loss of its interaction with junctional proteins, are also evident in RPE cells isolated from ccr2 −/− mice and from mice subjected to oxidative damage, both of which display age-related macular degeneration (AMD). Together, these results highlight an essential role for PTEN in normal RPE cell function and in the response of these cells to oxidative stress.[Keywords: PI3K signaling; PTEN; retinal pigment epithelium (RPE); epithelial-to-mesenchymal transition (EMT); age-related macular degeneration (AMD)] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

Kim¹,

Kang²,

Burrola³

et al. 2008

Genes Dev.

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“…These studies on the RCS rats are particularly interesting because the primary defect has been shown to reside in the inability of the pigment epithelia to appropriately phagocytose the disk packets shed from the ROS [130][131][132]. The aberrant cholesterol distribution may be a secondary effect of the mutation.…”

Section: Retinal Disease and Cholesterolmentioning

confidence: 99%

The role of cholesterol in rod outer segment membranes

Albert

Boesze‐Battaglia

2005

Progress in Lipid Research

112

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The photoreceptor rod outer segment (ROS) provides a unique system in which to investigate the role of cholesterol, an essential membrane constituent of most animal cells. The ROS is responsible for the initial events of vision at low light levels. It consists of a stack of disk membranes surrounded by the plasma membrane. Light capture occurs in the outer segment disk membranes that contain the photopigment, rhodopsin. These membranes originate from evaginations of the plasma membrane at the base of the outer segment. The new disks separate from the plasma membrane and progressively move up the length of the ROS over the course of several days. Thus the role of cholesterol can be evlauated in two distinct membranes. Furthermore, because the disk membranes vary in age it can also be investigated in a membrane as a function of the membrane age. The plasma membrane is enriched in cholesterol and in saturated fatty acids species relative to the disk membrane. The newly formed disk membranes have 6-fold more cholesterol than disks at the apical tip of the ROS. The partitioning of cholesterol out of disk membranes as they age and are apically displaced is consistent with the high PE content of disk membranes relative to the plasma membrane. The cholesterol composition of membranes has profound consequences on the major protein, rhodopsin. Biophysical studies in both model membranes and in native membranes have demonstrated that cholesterol can modulate the activity of rhodopsin by altering the membrane hydrocarbon environment. These studies suggest that mature disk membranes initiate the visual signal cascade more effectively than the newly synthesized, high cholesterol basal disks. Although rhodopsin is also the major protein of the plasma membrane, the high membrane cholesterol content inhibits rhodopsin participation in the visual transduction cascade. In addition to its effect on the hydrocarbon region, cholesterol may interact directly with rhodopsin. While high cholesterol inhibits rhodopsin activation, it also stabilizes the protein to denaturation. Therefore the disk membrane must perform a balancing act providing sufficient cholestrol to confer stability but without making the membrane too restrictive to receptor activation. Within a given disk membrane, it is likely that cholesterol exhibits an asymmetric distribution between the inner and outer bilayer leaflets. Furthremore, there is some evidence of cholesterol microdomains in the disk membranes. The availability of the disk protein, rom-1 may be sensitive to membrane cholesterol. The effects exerted by cholesterol on rhodopsin function have far-reaching implications for the study of G-protein coupled receptors as a whole. These studies show that the function of a membrane receptor can be modulated by modification of HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the lipid bilayer, particularly cholesterol. This provides a powerful means of fine-tuning the activity of a membrane protein without resorting ...

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“…Thus, an individual post-mitotic RPE cell disposes of several thousand outer segment membrane disks once a day for decades. Synchronized RPE phagocytosis is critical for vision since its deficiency causes blindness in human patients and in animal models (Edwards and Szamier, 1977;Gal et al, 2000;Nandrot et al, 2004;Scott et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Tetraspanin CD81 is required for the αvβ5-integrin-dependent particle-binding step of RPE phagocytosis

Chang

Finnemann

2007

Journal of Cell Science

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Retinal pigment epithelial (RPE) cells are among the most active phagocytes in the body. Every morning, circadian shedding of outer segment fragments by photoreceptor cells activates a synchronized phagocytic response by RPE cells that is critical for vision. RPE cells require αvβ5 integrin receptors for particle binding that triggers engulfment. Here, we show that tetraspanins CD81 and CD9 reside in a complex specifically with αvβ5 integrin but not the engulfment receptors Mer tyrosine kinase and CD36 at the apical, phagocytic surface of RPE cells. Function blocking and RNA silencing of CD81 but not of CD9 specifically diminish particle binding. CD81 but not CD9 overexpression is sufficient to increase particle binding and surface levels of αvβ5 integrin. Wild-type and mutant RPE cells defective in particle engulfment equally reduce and increase particle binding in response to CD81 inhibition and CD81 overexpression, respectively. By striking contrast, neither CD81 inhibition nor CD81 overexpression has any effect on particle binding by RPE lacking αvβ5 integrin. These results identify a novel and important role for CD81 in phagocytosis. CD81 does not function as a binding receptor by itself but promotes outer segment particle binding through functional interaction specifically with αvβ5 integrin.

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Defective Phagocytosis of Isolated Rod Outer Segments by RCS Rat Retinal Pigment Epithelium in Culture

Cited by 226 publications

References 13 publications

Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

Retinal degeneration triggered by inactivation of PTEN in the retinal pigment epithelium

The role of cholesterol in rod outer segment membranes

Tetraspanin CD81 is required for the αvβ5-integrin-dependent particle-binding step of RPE phagocytosis

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