Cited by 156Retinal Development and DisordersPhagocytosis and Immune RegulationRetinal Diseases and Treatments

Diurnal, localized exposure of phosphatidylserine by rod outer segment tips in wild-type but not Itgb5 −/− or Mfge8 −/− mouse retina

Open access
Ruggiero, Linda, Connor, Mark P., Chen, Jeannie, Langen, Ralf, Finnemann, Silvia C.·2012·Proceedings of the National Academy of Sciences

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1121101109

Cites

26 of 26 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The tips of OSs contain PS exposed to the extracellular space, especially at light onset.

    “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

  • Determination of the size of the phagocytic cup and the size of the ensuing phagosome likely involves an interaction between the pseudopodia and regulated features of the OS, such as PS exposure or the presence of open OS disks.

    “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

  • External PS localization at the tips of OSs is stimulated only in the presence of the RPE, since it requires the RPE integrin αvβ5 and its extracellular ligand MFGE8.

    “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

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
Published
2012-05-07
Volume
109
Issue
21
Pages
8145-8148
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review