title: Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.
abstract: 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.
authors: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Yaroslava
authors: Y
authors: Ruzankina
authors: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Carolina
authors: C
authors: Pinzon-Guzman
authors: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Amma
authors: A
authors: Asare
authors: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Tony
authors: T
authors: Ong
authors: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Laura
authors: L
authors: Pontano
authors: Department of Dermatology, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: George
authors: G
authors: Cotsarelis
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Valerie P
authors: VP
authors: Zediak
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Marielena
authors: M
authors: Velez
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors: Avinash
authors: A
authors: Bhandoola
authors: 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.
authors: Eric J
authors: EJ
authors: Brown
mesh_terms: 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*
chemical_list: D018797:Cell Cycle Proteins; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases