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.
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
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.