title: Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss.
abstract: Genome stability is essential for neural development and the prevention of neurological disease. Here we determined how DNA damage signaling from dysfunctional telomeres affects neurogenesis. We found that telomere uncapping by Pot1a inactivation resulted in an Atm-dependent loss of cerebellar interneurons and granule neuron precursors in the mouse nervous system. The activation of Atm by Pot1a loss occurred in an Atr-dependent manner, revealing an Atr to Atm signaling axis in the nervous system after telomere dysfunction. In contrast to telomere lesions, Brca2 inactivation in neural progenitors also led to ablation of cerebellar interneurons, but this did not require Atm. These data reveal that neural cell loss after DNA damage selectively engages Atm signaling, highlighting how specific DNA lesions can dictate neuropathology arising in human neurodegenerative syndromes.
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, Genomic Instability Research Center (GIRC), Ajou University School of Medicine, Suwon, Korea, peter.mckinnon@stjude.org ysoolee@ajou.ac.kr.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Abramson Family Cancer Research Institute and the Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, and.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.affiliation: Department of Laboratory Medicine, Yale University, New Haven, Connecticut 06520.
authors.forename: Sandy
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, peter.mckinnon@stjude.org ysoolee@ajou.ac.kr.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064231:Nestin / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D064231:Nestin; C507326:POT1 protein, mouse; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D001616:beta-Galactosidase
keywords: ATM; DNA damage; cerebellum; neural development; telomeres