A milk membrane glycoprotein, MFG-E8 [milk fat globule-EGF (epidermal growth factor) factor 8], is expressed abundantly in lactating mammary glands in stage- and tissue-specific manners, and has been believed to be secreted in association with milk fat globules. In the present paper, we describe further up-regulation of MFG-E8 in involuting mammary glands, where the glands undergo a substantial increase in the rate of epithelial cell apoptosis, and a possible role of MFG-E8 in mediating recognition and engulfment of apoptotic cells through its specific binding to PS (phosphatidylserine). Immunoblotting and RNA blotting analyses revealed that both MFG-E8 protein and MFG-E8 mRNA were markedly increased in mammary tissue within 3 days of either natural or forced weaning (pup withdrawal) of lactating mice. Using immunohistochemical analysis of the mammary tissue cryosections, the MFG-E8 signal was detected around the epithelium of such involuting mammary glands, but was almost undetectable at early- and mid-lactation stages, although strong signals were obtained for milk fat globules stored in the alveolar lumen. Some signals double positive to a macrophage differentiation marker, CD68, and MFG-E8 were detected in the post-weaning mammary tissue, although such double-positive signals were much smaller in number than the MFG-E8 single-positive ones. Total MFG-E8 in milk was also increased in the post-weaning mammary glands and, furthermore, the free MFG-E8 content in the post-weaning milk, as measured by in vitro PS-binding and apoptotic HC11 cell-binding activities, was much higher than that of lactation. In addition, the post-weaning milk enhanced the binding of apoptotic HC11 cells to J774 macrophages. Sucrose density-gradient ultracentrifugation analyses revealed that such enhanced PS-binding activity of MFG-E8 was present in membrane vesicle fractions (density 1.05–1.13 g/ml), rather than milk fat globule fractions. The weaning-induced MFG-E8 might play an important role in the recognition and engulfment of apoptotic epithelial cells by the neighbouring phagocytic epithelial cells in involuting mammary glands.
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Research Article|
March 15 2006
Weaning-induced expression of a milk-fat globule protein, MFG-E8, in mouse mammary glands, as demonstrated by the analyses of its mRNA, protein and phosphatidylserine-binding activity
Hajime Nakatani;
Hajime Nakatani
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Naohito Aoki;
Naohito Aoki
1
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
†Department of Life Sciences, Faculty of Bioresources, Mie University, 1577 Kurimamachiya-cho, Tsu 514-8507, Japan
1Correspondence may be addressed to either of these authors (email tmatsuda@agr.nagoya-u.ac.jp or n-aoki@bio.mie-u.ac.jp).
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Yoshimi Nakagawa;
Yoshimi Nakagawa
‡Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tennodai1-1-1, Tsukuba, Ibaraki, 305-8575, Japan
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Shinji Jin-No;
Shinji Jin-No
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Koji Aoyama;
Koji Aoyama
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Kenji Oshima;
Kenji Oshima
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Sachiyo Ohira;
Sachiyo Ohira
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Chihiro Sato;
Chihiro Sato
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Daita Nadano;
Daita Nadano
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
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Tsukasa Matsuda
Tsukasa Matsuda
1
*Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
1Correspondence may be addressed to either of these authors (email tmatsuda@agr.nagoya-u.ac.jp or n-aoki@bio.mie-u.ac.jp).
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Publisher: Portland Press Ltd
Received:
September 02 2005
Revision Received:
January 03 2006
Accepted:
January 09 2006
Accepted Manuscript online:
January 09 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 395 (1): 21–30.
Article history
Received:
September 02 2005
Revision Received:
January 03 2006
Accepted:
January 09 2006
Accepted Manuscript online:
January 09 2006
Citation
Hajime Nakatani, Naohito Aoki, Yoshimi Nakagawa, Shinji Jin-No, Koji Aoyama, Kenji Oshima, Sachiyo Ohira, Chihiro Sato, Daita Nadano, Tsukasa Matsuda; Weaning-induced expression of a milk-fat globule protein, MFG-E8, in mouse mammary glands, as demonstrated by the analyses of its mRNA, protein and phosphatidylserine-binding activity. Biochem J 1 April 2006; 395 (1): 21–30. doi: https://doi.org/10.1042/BJ20051459
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