The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis
Open accessAbstract
The integrin receptor alphavbeta5 controls two independent forms of interactions of the retinal pigment epithelium (RPE) with adjacent photoreceptor outer segments that are essential for vision. Alphavbeta5 localizes specifically to apical microvilli of the RPE and contributes to retinal adhesion that maintains RPE contacts with intact outer segments at all times. Additionally, alphavbeta5 synchronizes diurnal bursts of RPE phagocytosis that clear photoreceptor outer segment fragments (POS) shed in a circadian rhythm. Dependence of retinal phagocytosis and adhesion on alphavbeta5 receptors suggests that the extracellular matrix ensheathing RPE microvilli contains ligands for this integrin. Here we studied mice lacking expression of functional MFG-E8 to test the contribution of this integrin ligand to alphavbeta5 functions in the retina. Lack of MFG-E8 only minimally reduced retinal adhesion. In contrast, lack of MFG-E8, like lack of alphavbeta5 receptor, eliminated alphavbeta5 downstream signaling involving the engulfment receptor MerTK and peak POS phagocytosis, both of which follow light onset in wild-type retina. MFG-E8-deficient RPE in primary culture retained normal epithelial morphology and levels of apical alphavbeta5 receptors, but showed impaired binding and engulfment of isolated POS. Soluble or POS-bound recombinant MFG-E8 was sufficient to fully restore phagocytosis by MFG-E8-deficient RPE. Furthermore, MFG-E8 supplementation strongly increased POS binding by wild-type and MerTK-deficient RPE, but did not affect POS binding by RPE lacking alphavbeta5. Thus, MFG-E8 stimulates rhythmic POS phagocytosis by ligating apical alphavbeta5 receptors of the RPE. These results identify MFG-E8 as the first extracellular ligand in the retina that is essential for diurnal POS phagocytosis.
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“Perhaps surprisingly, MFGE8, as the bridging molecule linking αvβ5 to the OS, plays only a minor role in retinal adhesion (Nandrot et al., 2007).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Nandrot et al., 2007
In the citing paper
“OS phagocytosis is similarly arrhythmic, but not blocked in Mfge8−/− mice (Nandrot et al., 2007).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Nandrot et al., 2007
In the citing paper
“Strikingly, we found that Atg5 co-localized with engulfed POS in control mice (Figure 3A, arrows merged image) (visualized by rhodopsin staining (Nandrot et al., 2007)) as well as with LC3 in the GFP-LC3 transgenic mice (Figure 3C, arrows).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Nandrot et al., 2007
In the citing paper
“Secondary effects on the expression of receptors involved in POS binding and phagocytosis (Gal et al., 2000; Nandrot et al., 2007; Nandrot et al., 2004) due to the deletion of Atg5 were not observed in Atg5ΔRPE RPE cells compared to control (Figure S1).”
From Noncanonical autophagy promotes the visual cycle (2013) · cites this paper as Nandrot et al., 2007
In the citing paper
“Photoreceptor tip shedding occurs throughout the day, but it is maximal in the morning just after the onset of the light cycle, [8][9][10] linking the process to circadian rhythms.41,51”
From RUBCN/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye (2017) · cites this paper as [41]
Citations
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Self-citationApoptotic photoreceptor degeneration in experimental retinal detachment.
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Loss of synchronized retinal phagocytosis and age-related blindness in mice lacking αvβ5 integrin
Nandrot, E. F., Kim, Y., Brodie, S. E., Huang, X., Sheppard, D., & Finnemann, S. C. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041447 · Cited by 319
Self-citationTAM receptor function in the retinal pigment epithelium
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Self-citationFocal adhesion kinase signaling promotes phagocytosis of integrin‐bound photoreceptors
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Self-citation
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Cahoy, J. D., Emery, B., Kaushal, A., Foo, L. C., Zamanian, J. L., Christopherson, K. S., Xing, Y., Lubischer, J. L., Krieg, P. A., Krupenko, S. A., et al. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4178-07.2008 · Cited by 3,129
“…we also identified the Mertk/ Axl, v 5 integrin pathway previously shown to mediate phagocytosis of shedding rod outer segments by retinal pigment epithelial cells (Feng et al., 2002; Duncan et al., 2003; Finnemann and Nandrot, 2006; Nandrot et al., 2007), as highly enriched in astrocytes in vivo.”
BackgroundClearance of apoptotic cells: implications in health and disease
Elliott, M. R., & Ravichandran, K. S. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.201004096 · Cited by 568
Getting to the Outer Leaflet: Physiology of Phosphatidylserine Exposure at the Plasma Membrane
Bevers, E. M., & Williamson, P. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00020.2015 · Cited by 457
Phagocytosis of Retinal Rod and Cone Photoreceptors
Kevany, B. M., & Palczewski, K. (2010) · Physiology · doi:10.1152/physiol.00038.2009 · Cited by 426
The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422
Metadata
- Authors
- Nandrot, E. F., Anand, M., Almeida, D., Atabai, K., Sheppard, D., & Finnemann, S. C.
- Affiliations
- Cornell University (US)
- *Dyson Vision Research Institute, Department of Ophthalmology,
- University of California, San Francisco (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-07-17
- Volume
- 104
- Issue
- 29
- Pages
- 12005-12010
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1924559
- OpenAlex
- W1993913137
- Cited by
- 241
- References
- 17
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 14 · 2023: 12 · 2022: 15 · 2021: 22 · 2020: 17 · 2019: 7 · 2018: 18 · 2017: 12 · 2016: 10 · 2015: 10 · 2014: 18 · 2013: 15 · 2012: 14
- FWCI
- 3.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Research to Prevent Blindness
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-83985, K08HL083985, HL-66600, U01HL066600)
- National Eye Institute (R01EY013295, EY-13295, R21EY017173, EY-13173)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- MFG-E8, integrin αvβ5, retinal pigment epithelium, photoreceptor outer segment phagocytosis, circadian rhythm, MERTK, integrin ligands, retinal adhesion, microvilli, engulfment receptor
- MeSH terms
- c-Mer Tyrosine Kinase, Animals, Antigens, Surface, Cell Adhesion, Circadian Rhythm, Enzyme Activation, Ligands, Milk Proteins, Phagocytosis, Phenotype, Pigment Epithelium of Eye, Protein Binding, Proto-Oncogene Proteins, Recombinant Proteins, Rod Cell Outer Segment, Solubility, Integrins, Receptors, Vitronectin, Receptor Protein-Tyrosine Kinases, Mutant Proteins, Mice
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