Programmed cell senescence during mammalian embryonic development.
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.
Tumor Suppression Group, Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
Daniel
D
Muñoz-Espín
Marta
M
Cañamero
Antonio
A
Maraver
Gonzalo
G
Gómez-López
Julio
J
Contreras
Silvia
S
Murillo-Cuesta
Alfonso
A
Rodríguez-Baeza
Isabel
I
Varela-Nieto
Jesús
J
Ruberte
Manuel
M
Collado
Manuel
M
Serrano
D000818:Animals; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D047108:Embryonic Development; D004712:Endolymphatic Sac / Q000166:cytology / Q000196:embryology*; D005260:Female; D006801:Humans; D007668:Kidney / Q000196:embryology; D008297:Male; D008650:Mesonephros / Q000166:cytology / Q000196:embryology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases