Rac1 controls cell turnover and mammary gland reversibility in post-partum involution

Abstract

Cell turnover in adult tissues is essential for maintaining tissue homeostasis over a lifespan and for inducing the morphological changes associated with the reproductive cycle. However, the underlying mechanisms that coordinate the balance of cell death and proliferation remain unsolved. Using the mammary gland we have discovered that Rac1 acts as a nexus to control cell turnover. Post-lactational tissue regression is characterized by the death of milk secreting alveoli, but the process is reversible within the first 48h if feeding recommences. In mice lacking epithelial Rac1, alveolar regression was delayed. This defect did not result from failed cell death but rather increased cell turnover. Fitter progenitor cells inappropriately divided, regenerating the alveoli but cell death also concomitantly accelerated. We discovered that progenitor cell hyperproliferation was linked to non-autonomous effects of Rac1 deletion on the macrophageal niche with heightened inflammation. Moreover, loss of Rac1 impaired cell death with autophagy but switched the cell death route to apoptosis. Finally, mammary gland reversibility failed in the absence of Rac1 as the regenerated alveoli failed to recommence lactation upon re-suckling.