Abstract
SummaryAn 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.
Highlights
The removal of surplus cells is crucial for tissue remodeling during development, and for the maintenance of organ homeostasis
While numerous studies have focused on the process of epithelial cell death, it is unclear how cell corpses are removed or how this influences subsequent tissue remodeling
Rac1 controls the lactational differentiation of cultured mammary epithelial cells (MECs) alveoli downstream of b1-integrin (Akhtar et al, 2009; Akhtar and Streuli, 2006; Naylor et al, 2005), and here we investigated the role of Rac1 in mammary epithelia at the genetic level
Summary
The removal of surplus cells is crucial for tissue remodeling during development, and for the maintenance of organ homeostasis. One tissue that can assist in understanding the molecular basis of epithelial remodeling and tissue-specific function is the mammary gland. This tissue moderately proliferates and regresses with each menstrual cycle, but undergoes extreme expansion and regression during pregnancy, lactation, and involution. Involution occurs when the offspring stop suckling It is characterized by a cessation of milk production followed by massive cell death of the secretory alveolar units, leaving the ductal tree behind (Atabai et al, 2007; Watson, 2006). While numerous studies have focused on the process of epithelial cell death, it is unclear how cell corpses are removed or how this influences subsequent tissue remodeling. The mechanism that determines this switch is not known
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