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Cited by 243Retinal Development and DisordersRetinal Diseases and TreatmentsCell Adhesion Molecules Research

Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis

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Nandrot, Emeline F., Anand, Monika, Almeida, Dena, Atabai, Kamran, Sheppard, Dean, Finnemann, Silvia C.·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0704756104PMC PMC1924559
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Abstract

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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Crossref · 10.1073/pnas.0704756104

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  • MFGE8 plays only a minor role in retinal adhesion.

    “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

  • OS phagocytosis is arrhythmic, but not blocked in Mfge8−/− mice.

    “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

  • Atg5 co-localizes with engulfed POS in control mice.

    “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

  • Secondary effects on the expression of receptors involved in POS binding and phagocytosis due to the deletion of Atg5 were not observed in Atg5ΔRPE RPE cells compared to control.

    “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

  • Photoreceptor tip shedding is maximal in the morning just after onset of the light cycle, linking the process to circadian rhythms.

    “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]

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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)
ORCID
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
DOI
10.1073/pnas.0704756104
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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