Rac1 Controls Both the Secretory Function of the Mammary Gland and Its Remodeling for Successive Gestations.
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.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK; Department of Oncology and Metabolism, The Bateson Centre, University of Sheffield, Beech Hill Road, Sheffield S10 2RX, UK. Electronic address: n.akhtar@sheffield.ac.uk.
Nasreen
N
Akhtar
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Weiping
W
Li
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Aleksander
A
Mironov
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, and Manchester Breast Centre, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
Charles H
CH
Streuli
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D042361:Mammary Glands, Human / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D018345:Mice, Knockout; D010586:Phagocytes / Q000378:metabolism; D011247:Pregnancy; D012038:Regeneration / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics*
D020830:rac1 GTP-Binding Protein
Rac1; ducts; inflammation; involution; lactation; mammary; phagocytosis; regeneration