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      Rac1 Controls Both the Secretory Function of the Mammary Gland and Its Remodeling for Successive Gestations

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          Summary

          An important feature of the mammary gland is its ability to undergo repeated morphological changes during each reproductive cycle with profound tissue expansion in pregnancy and regression in involution. However, the mechanisms that determine the tissue's cyclic regenerative capacity remain elusive. We have now discovered that Cre-Lox ablation of Rac1 in mammary epithelia causes gross enlargement of the epithelial tree and defective alveolar regeneration in a second pregnancy. Architectural defects arise because loss of Rac1 disrupts clearance in involution following the first lactation. We show that Rac1 is crucial for mammary alveolar epithelia to switch from secretion to a phagocytic mode and rapidly remove dying neighbors. Moreover, Rac1 restricts the extrusion of dying cells into the lumen, thus promoting their eradication by live phagocytic neighbors while within the epithelium. Without Rac1, residual milk and cell corpses flood the ductal network, causing gross dilation, chronic inflammation, and defective future regeneration.

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          Highlights

          • Rac1 is required for full secretory differentiation of the mammary gland

          • Rac1 restricts apoptotic cell shedding into the lumen to limit inflammation

          • Rac1 contributes to post-lactational tissue remodeling during involution

          • Defective clearance of milk and dead cells in Rac1-null glands causes ductal bloating

          Abstract

          Akhtar et al. show that Rac1 gene deletion disrupts mammary gland development and causes long-term tissue malfunction. In lactation, Rac1 is required for milk production. After lactation, Rac1 causes cell function to switch from secretion to phagocytosis, thereby removing apoptotic cells and excess milk. This allows the tissue to remodel for the next pregnancy.

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          Most cited references26

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          Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.

          During normal tissue remodeling, macrophages remove unwanted cells, including those that have undergone programmed cell death, or apoptosis. This widespread process extends to the deletion of thymocytes (negative selection), in which cells expressing inappropriate Ag receptors undergo apoptosis, and are phagocytosed by thymic macrophages. Although phagocytosis of effete leukocytes by macrophages has been known since the time of Metchnikoff, only recently has it been recognized that apoptosis leads to surface changes that allow recognition and removal of these cells before they are lysed. Our data suggest that macrophages specifically recognize phosphatidylserine that is exposed on the surface of lymphocytes during the development of apoptosis. Macrophage phagocytosis of apoptotic lymphocytes was inhibited, in a dose-dependent manner, by liposomes containing phosphatidyl-L-serine, but not by liposomes containing other anionic phospholipids, including phosphatidyl-D-serine. Phagocytosis of apoptotic lymphocytes was also inhibited by the L isoforms of compounds structurally related to phosphatidylserine, including glycerophosphorylserine and phosphoserine. The membranes of apoptotic lymphocytes bound increased amounts of merocyanine 540 dye relative to those of normal cells, indicating that their membrane lipids were more loosely packed, consistent with a loss of membrane phospholipid asymmetry. Apoptotic lymphocytes were shown to express phosphatidylserine (PS) externally, because PS on their surfaces was accessible to derivatization by fluorescamine, and because apoptotic cells expressed procoagulant activity. These observations suggest that apoptotic lymphocytes lose membrane phospholipid asymmetry and expose phosphatidylserine on the outer leaflet of the plasma membrane. Macrophages then phagocytose apoptotic lymphocytes after specific recognition of the exposed PS.
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            Autoimmunity and the clearance of dead cells.

            To maintain organismal homeostasis, phagocytes engulf dead cells, which are recognized as dead by virtue of a characteristic "eat me" signal exposed on their surface. The dead cells are then transferred to lysosomes, where their cellular components are degraded for reuse. Inefficient engulfment of dead cells activates the immune system, causing disease such as systemic lupus erythematosus, and if the DNA of the dead cells is not properly degraded, the innate immune response becomes activated, leading to severe anemia and chronic arthritis. Here, we discuss how the endogenous components of dead cells activate the immune system through both extracellular and intracellular pathways. (c) 2010 Elsevier Inc. All rights reserved.
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              Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion.

              Clearance of apoptotic cells is the final stage of programmed cell death. Uncleared corpses can become secondarily necrotic, promoting inflammation and autoimmunity. Remarkably, even in tissues with high cellular turnover, apoptotic cells are rarely seen because of efficient clearance mechanisms in healthy individuals. Recently, significant progress has been made in understanding the steps involved in prompt cell clearance in vivo. These include the sensing of corpses via "find me" signals, the recognition of corpses via "eat me" signals and their cognate receptors, the signaling pathways that regulate cytoskeletal rearrangement necessary for engulfment, and the responses of the phagocyte that keep cell clearance events "immunologically silent." This study focuses on our understanding of these steps.
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                Author and article information

                Contributors
                Journal
                Dev Cell
                Dev. Cell
                Developmental Cell
                Cell Press
                1534-5807
                1878-1551
                12 September 2016
                12 September 2016
                : 38
                : 5
                : 522-535
                Affiliations
                [1 ]Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK
                [2 ]Department of Oncology and Metabolism, The Bateson Centre, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK
                Author notes
                []Corresponding author n.akhtar@ 123456sheffield.ac.uk
                [3]

                Lead Contact

                Article
                S1534-5807(16)30580-9
                10.1016/j.devcel.2016.08.005
                5022528
                27623383
                73a70b45-4022-4ebc-b03a-8547aada6a81
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 October 2015
                : 30 June 2016
                : 12 August 2016
                Categories
                Article

                Developmental biology
                mammary,rac1,lactation,ducts,involution,phagocytosis,inflammation,regeneration
                Developmental biology
                mammary, rac1, lactation, ducts, involution, phagocytosis, inflammation, regeneration

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