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Science 302 (5650): 1560-1563

Copyright © 2003 by the American Association for the Advancement of Science

Phosphatidylserine Receptor Is Required for Clearance of Apoptotic Cells

Ming O. Li,1,3* Matthew R. Sarkisian,2* Wajahat Z. Mehal,1,4 Pasko Rakic,2 Richard A. Flavell1,3{dagger}

Abstract: Cells undergoing apoptosis during development are removed by phagocytes, but the underlying mechanisms of this process are not fully understood. Phagocytes lacking the phosphatidylserine receptor (PSR) were defective in removing apoptotic cells. Consequently, in PSR-deficient mice, dead cells accumulated in the lung and brain, causing abnormal development and leading to neonatal lethality. A fraction of PSR knockout mice manifested a hyperplasic brain phenotype resembling that of mice deficient in the cell death–associated genes encoding Apaf-1, caspase-3, and caspase-9, which suggests that phagocytes may also be involved in promoting apoptosis. These data demonstrate a critical role for PSR in early stages of mammalian organogenesis and suggest that this receptor may be involved in respiratory distress syndromes and congenital brain malformations.

1 Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
2 Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
3 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
4 Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.

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* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: richard.flavell{at}

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F. Jansen, X. Yang, F. F. Hoyer, K. Paul, N. Heiermann, M. U. Becher, N. A. Hussein, M. Kebschull, J. Bedorf, B. S. Franklin, et al. (2012)
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   Abstract »    Full Text »    PDF »
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Y.-i. Tsukada (2012)
J. Biochem. 151, 229-246
   Abstract »    Full Text »    PDF »
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M. Fricker, J. J. Neher, J.-W. Zhao, C. Thery, A. M. Tolkovsky, and G. C. Brown (2012)
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   Abstract »    Full Text »    PDF »
NF-{kappa}B Signaling in Fetal Lung Macrophages Disrupts Airway Morphogenesis.
T. S. Blackwell, A. N. Hipps, Y. Yamamoto, W. Han, W. J. Barham, M. C. Ostrowski, F. E. Yull, and L. S. Prince (2011)
J. Immunol. 187, 2740-2747
   Abstract »    Full Text »    PDF »
Small-Animal PET of Tumor Damage Induced by Photothermal Ablation with 64Cu-Bis-DOTA-Hypericin.
S. Song, C. Xiong, M. Zhou, W. Lu, Q. Huang, G. Ku, J. Zhao, L. G. Flores Jr., Y. Ni, and C. Li (2011)
J. Nucl. Med. 52, 792-799
   Abstract »    Full Text »    PDF »
Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death.
J. J. Neher, U. Neniskyte, J.-W. Zhao, A. Bal-Price, A. M. Tolkovsky, and G. C. Brown (2011)
J. Immunol. 186, 4973-4983
   Abstract »    Full Text »    PDF »
Interaction of JMJD6 with single-stranded RNA.
X. Hong, J. Zang, J. White, C. Wang, C.-H. Pan, R. Zhao, R. C. Murphy, S. Dai, P. Henson, J. W. Kappler, et al. (2010)
PNAS 107, 14568-14572
   Abstract »    Full Text »    PDF »
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R. Maghdessian, F. Cote, T. Rouleau, A. B. D. Ouadda, E. Levy, and J.-C. Lavoie (2010)
J. Pharmacol. Exp. Ther. 334, 278-284
   Abstract »    Full Text »    PDF »
Jmjd6 Catalyses Lysyl-Hydroxylation of U2AF65, a Protein Associated with RNA Splicing.
C. J. Webby, A. Wolf, N. Gromak, M. Dreger, H. Kramer, B. Kessler, M. L. Nielsen, C. Schmitz, D. S. Butler, J. R. Yates III, et al. (2009)
Science 325, 90-93
   Abstract »    Full Text »    PDF »
Thematic Review Series: Glycerolipids. Phosphatidylserine and phosphatidylethanolamine in mammalian cells: two metabolically related aminophospholipids.
J. E. Vance (2008)
J. Lipid Res. 49, 1377-1387
   Abstract »    Full Text »    PDF »
What makes a dead cell attractive?.
J. P. Konhilas (2008)
J Appl Physiol 104, 573-574
   Full Text »    PDF »
Apoptotic myocytes generate monocyte chemoattractant protein-1 and mediate macrophage recruitment.
M. Kobara, N. Sunagawa, M. Abe, N. Tanaka, H. Toba, H. Hayashi, N. Keira, T. Tatsumi, H. Matsubara, and T. Nakata (2008)
J Appl Physiol 104, 601-609
   Abstract »    Full Text »    PDF »
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B. N. Y. Setty and S. G. Betal (2008)
Blood 111, 905-914
   Abstract »    Full Text »    PDF »
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K. A. Kevill, V. Bhandari, M. Kettunen, L. Leng, J. Fan, Y. Mizue, J. D. Dzuira, M. Reyes-Mugica, C. L. McDonald, J. A. Baugh, et al. (2008)
J. Immunol. 180, 601-608
   Abstract »    Full Text »    PDF »
Persistent activation of microglia is associated with neuronal dysfunction of callosal projecting pathways and multiple sclerosis-like lesions in relapsing remitting experimental autoimmune encephalomyelitis.
S. Rasmussen, Y. Wang, P. Kivisakk, R. T. Bronson, M. Meyer, J. Imitola, and S. J. Khoury (2007)
Brain 130, 2816-2829
   Abstract »    Full Text »    PDF »
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B. Chang, Y. Chen, Y. Zhao, and R. K. Bruick (2007)
Science 318, 444-447
   Abstract »    Full Text »    PDF »
P.S. to PS (Phosphatidylserine) Pertinent Proteins in Apoptotic Cell Clearance.
R. A. Schlegel and P. Williamson (2007)
Sci. STKE 2007, pe57
   Abstract »    Full Text »    PDF »
The Drosophila homolog of the putative phosphatidylserine receptor functions to inhibit apoptosis.
R. J. Krieser, F. E. Moore, D. Dresnek, B. J. Pellock, R. Patel, A. Huang, C. Brachmann, and K. White (2007)
Development 134, 2407-2414
   Abstract »    Full Text »    PDF »
Changing story of the receptor for phosphatidylserine-dependent clearance of apoptotic cells.
A. Wolf, C. Schmitz, and A. Bottger (2007)
EMBO Rep. 8, 465-469
   Abstract »    Full Text »    PDF »
Macrophages and Dendritic Cells Use Different Axl/Mertk/Tyro3 Receptors in Clearance of Apoptotic Cells.
H. M. Seitz, T. D. Camenisch, G. Lemke, H. S. Earp, and G. K. Matsushima (2007)
J. Immunol. 178, 5635-5642
   Abstract »    Full Text »    PDF »
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D. M. Schrijvers, G. R.Y. De Meyer, A. G. Herman, and W. Martinet (2007)
Cardiovasc Res 73, 470-480
   Abstract »    Full Text »    PDF »
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A. Sturm, R. Amino, C. van de Sand, T. Regen, S. Retzlaff, A. Rennenberg, A. Krueger, J.-M. Pollok, R. Menard, and V. T. Heussler (2006)
Science 313, 1287-1290
   Abstract »    Full Text »    PDF »
Recognition ligands on apoptotic cells: a perspective.
S. J. Gardai, D. L. Bratton, C. A. Ogden, and P. M. Henson (2006)
J. Leukoc. Biol. 79, 896-903
   Abstract »    Full Text »    PDF »
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J. E. Mitchell, M. Cvetanovic, N. Tibrewal, V. Patel, O. R. Colamonici, M. O. Li, R. A. Flavell, J. S. Levine, R. B. Birge, and D. S. Ucker (2006)
J. Biol. Chem. 281, 5718-5725
   Abstract »    Full Text »    PDF »
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H. Yuita, M. Tsuiji, Y. Tajika, Y. Matsumoto, K. Hirano, N. Suzuki, and T. Irimura (2005)
Glycobiology 15, 1368-1375
   Abstract »    Full Text »    PDF »
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Biol Res Nurs 7, 118-129
   Abstract »    PDF »
Immunoregulation of Dendritic Cells.
M. A Wallet, P. Sen, and R. Tisch (2005)
Clin. Med. Res. 3, 166-175
   Abstract »    Full Text »    PDF »
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G. Tunheim, K. W. Schjetne, A. B. Fredriksen, I. Sandlie, and B. Bogen (2005)
J. Leukoc. Biol. 77, 303-310
   Abstract »    Full Text »    PDF »
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P. R. Hoffmann, J. A. Kench, A. Vondracek, E. Kruk, D. L. Daleke, M. Jordan, P. Marrack, P. M. Henson, and V. A. Fadok (2005)
J. Immunol. 174, 1393-1404
   Abstract »    Full Text »    PDF »
Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/- mice.
A. Devitt, K. G. Parker, C. A. Ogden, C. Oldreive, M. F. Clay, L. A. Melville, C. O. Bellamy, A. Lacy-Hulbert, S. C. Gangloff, S. M. Goyert, et al. (2004)
J. Cell Biol. 167, 1161-1170
   Abstract »    Full Text »    PDF »
VP1 of Foot-and-Mouth Disease Virus Induces Apoptosis via the Akt Signaling Pathway.
J.-M. Peng, S.-M. Liang, and C.-M. Liang (2004)
J. Biol. Chem. 279, 52168-52174
   Abstract »    Full Text »    PDF »
Draper-mediated and Phosphatidylserine-independent Phagocytosis of Apoptotic Cells by Drosophila Hemocytes/Macrophages.
J. Manaka, T. Kuraishi, A. Shiratsuchi, Y. Nakai, H. Higashida, P. Henson, and Y. Nakanishi (2004)
J. Biol. Chem. 279, 48466-48476
   Abstract »    Full Text »    PDF »
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J.-C. Lavoie, T. Rouleau, and P. Chessex (2004)
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   Abstract »    Full Text »    PDF »
Inhibition of Phosphatidylserine Recognition Heightens the Immunogenicity of Irradiated Lymphoma Cells In Vivo.
A. Bondanza, V. S. Zimmermann, P. Rovere-Querini, J. Turnay, I. E. Dumitriu, C. M. Stach, R. E. Voll, U. S. Gaipl, W. Bertling, E. Poschl, et al. (2004)
J. Exp. Med. 200, 1157-1165
   Abstract »    Full Text »    PDF »
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J.-R. Hong, G.-H. Lin, C. J.-F. Lin, W.-p. Wang, C.-C. Lee, T.-L. Lin, and J.-L. Wu (2004)
Development 131, 5417-5427
   Abstract »    Full Text »    PDF »
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M. J. McConnell, D. Kaushal, A. H. Yang, M. A. Kingsbury, S. K. Rehen, K. Treuner, R. Helton, E. G. Annas, J. Chun, and C. Barlow (2004)
J. Neurosci. 24, 8090-8096
   Abstract »    Full Text »    PDF »
Phosphatidylserine externalization in cardiolipin-deficient cells.
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Blood 104, 1582-1584
   Full Text »    PDF »
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K. Gurnani, J. Kennedy, S. Sad, G. D. Sprott, and L. Krishnan (2004)
J. Immunol. 173, 566-578
   Abstract »    Full Text »    PDF »
Clearance receptor controls death and differentiation.
S. Gordon (2004)
Blood 103, 3250
   Full Text »    PDF »
Defective fetal liver erythropoiesis and T lymphopoiesis in mice lacking the phosphatidylserine receptor.
Y. Kunisaki, S. Masuko, M. Noda, A. Inayoshi, T. Sanui, M. Harada, T. Sasazuki, and Y. Fukui (2004)
Blood 103, 3362-3364
   Abstract »    Full Text »    PDF »
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J. Savill, C. Gregory, and C. Haslett (2003)
Science 302, 1516-1517
   Abstract »    Full Text »    PDF »

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