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Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5 −/− or Mfge8 −/− mouse retina
Open accessAbstract
In the mammalian retina, life-long renewal of light-sensitive photoreceptor outer segments (POS) involves circadian shedding of distal rod POS tips and their subsequent phagocytosis by the adjacent retinal pigment epithelium (RPE) every morning after light onset. Molecular mechanisms that promote or synchronize POS tip shedding have thus far remained unknown. Here we examined plasma membrane asymmetry of living POS by quantifying surface exposure of the membrane phospholipid phosphatidylserine (PS) using antibodies, annexin V, and pSIVA (polarity-sensitive indicator of viability and apoptosis), an annexin-based biosensor with switchable states of fluorescence. We found that isolated POS particles possess externalized PS, whose blockade or removal reduces their binding and engulfment by RPE in culture. Imaging of live photoreceptors in freshly dissected mouse retina detected PS externalization restricted to POS tips with discrete boundaries. In wild-type mice, frequency of rod tips exposing PS and length of tips with exposed PS peak shortly after light onset. In contrast, PS-marked POS tips do not vary in mice lacking the diurnal phagocytic rhythm of the RPE due to loss of either the phagocytosis receptor αvβ5 integrin, expressed by the RPE but not by photoreceptors, or its extracellular ligand milk fat globule-EGF factor 8 (MFG-E8). These data identify a molecular distinction, localized PS exposure, that is specific to the surface of rod POS tips. Enhanced PS exposure preceding rod shedding and phagocytosis suggests that surface PS promotes these processes. Moreover, our results demonstrate that the diurnal rhythm of PS demarcation of POS tips is not intrinsic to rod photoreceptors but requires activities of the RPE as well.
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“the tips of OSs were found to contain PS exposed to the extracellular space, especially at light onset, using the PS-specific dye, pSIVA, a “polarity-sensitive indicator of viability and apoptosis” (Ruggiero et al., 2012)”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Ruggiero et al., 2012
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“Similarly, determination of the size of the phagocytic cup, and the size of the ensuing phagosome is likely to involve an interaction between the pseudopodia and regulated features of the OS, such as PS exposure (see section 3.4 (Ruggiero et al., 2012);) or the presence of open OS disks (Matsumoto and Besharse, 1985).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Ruggiero et al., 2012
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“The external PS localization at the tips of OSs, mentioned above, is stimulated only in the presence of the RPE, since it requires the RPE integrin, αvβ5, and its extracellular ligand, MFGE8 (Ruggiero et al., 2012).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Ruggiero et al., 2012
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Metadata
- Authors
- Ruggiero, L., Connor, M. P., Chen, J., Langen, R., & Finnemann, S. C.
- Affiliations
- Fordham University (US)
- Departments of bCell and Neurobiology and
- University of Southern California (US)
- Corresponding author
- Finnemann, Silvia C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-05-07
- Volume
- 109
- Issue
- 21
- Pages
- 8145-8148
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3361434
- OpenAlex
- W2148756146
- Cited by
- 156
- References
- 26
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 8 · 2023: 14 · 2022: 16 · 2021: 11 · 2020: 17 · 2019: 6 · 2018: 11 · 2017: 15 · 2016: 9 · 2015: 10 · 2014: 13 · 2013: 6 · 2012: 1
- FWCI
- 3.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Eye Institute (EY-12155, R01EY013295, EY-13295, R01EY012155)
- National Institute of General Medical Sciences (R01GM063915, GM063915)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- phosphatidylserine exposure, diurnal cycle, alpha v beta 5 integrin, MFG-E8, membrane asymmetry, annexin V, circadian rhythm
- MeSH terms
- Animals, Antigens, Surface, Cell Membrane, Cells, Cultured, Circadian Rhythm, Light, Mice, Mutant Strains, Milk Proteins, Phagocytosis, Phosphatidylserines, Rod Cell Outer Segment, Apoptosis, Integrin beta Chains, Mice, Retinal Pigment Epithelium, Mice, 129 Strain
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