Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.
Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.
Ruzankina
Yaroslava
Y
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Pinzon-Guzman
Carolina
C
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Asare
Amma
A
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Ong
Tony
T
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Pontano
Laura
L
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Cotsarelis
George
G
Department of Dermatology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Zediak
Valerie P
VP
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Velez
Marielena
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Bhandoola
Avinash
A
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
Brown
Eric J
EJ
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA. Electronic address: brownej@mail.med.upenn.edu.
D000375:Aging / Q000235:genetics*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D020043:Genes, Essential; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology*
D018797:Cell Cycle Proteins; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases