Programmed Cell Senescence during Mammalian Embryonic Development

• Published in: Cell Vol. 155; no. 5; pp. 1104 - 1118
• Main Authors: Muñoz-Espín, Daniel, Cañamero, Marta, Maraver, Antonio, Gómez-López, Gonzalo, Contreras, Julio, Murillo-Cuesta, Silvia, Rodríguez-Baeza, Alfonso, Varela-Nieto, Isabel, Ruberte, Jesús, Collado, Manuel, Serrano, Manuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.11.2013
• Subjects: abnormal development; Animals; apoptosis; cell cycle; cell senescence; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA damage; ears; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; embryogenesis; Embryonic Development; Endolymphatic Sac - cytology; Endolymphatic Sac - embryology; Female; Humans; Kidney - embryology; macrophages; Male; Mesonephros - cytology; Mesonephros - embryology; Mice; Phosphatidylinositol 3-Kinases - metabolism; Signal Transduction; Smad Proteins - metabolism; Transforming Growth Factor beta - metabolism
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2013.10.019

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence. [Display omitted] •Senescence occurs in a programmed manner during normal mammalian development•The studied processes of senescence depend on p21 and the TGF-β and PI3K pathways•Senescent cells are cleared by macrophages, which results in tissue remodeling•Loss of senescence affects morphogenesis despite partial compensation by apoptosis Senescence occurs during normal mammalian embryonic development at precisely defined locations and stages, where it participates in tissue remodeling and morphogenesis.