title: ATR maintains select progenitors during nervous system development.
abstract: The ATR (ATM (ataxia telangiectasia mutated) and rad3-related) checkpoint kinase is considered critical for signalling DNA replication stress and its dysfunction can lead to the neurodevelopmental disorder, ATR-Seckel syndrome. To understand how ATR functions during neurogenesis, we conditionally deleted Atr broadly throughout the murine nervous system, or in a restricted manner in the dorsal telencephalon. Unexpectedly, in both scenarios, Atr loss impacted neurogenesis relatively late during neural development involving only certain progenitor populations. Whereas the Atr-deficient embryonic cerebellar external germinal layer underwent p53- (and p16(Ink4a/Arf))-independent proliferation arrest, other brain regions suffered apoptosis that was partially p53 dependent. In contrast to other organs, in the nervous system, p53 loss did not worsen the outcome of Atr inactivation. Coincident inactivation of Atm also did not affect the phenotype after Atr deletion, supporting non-overlapping physiological roles for these related DNA damage-response kinases in the brain. Rather than an essential general role in preventing replication stress, our data indicate that ATR functions to monitor genomic integrity in a selective spatiotemporal manner during neurogenesis.
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.forename: Erin R P
authors.initials: ER
authors.lastname: Shull
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Frappart
authors.forename: Sachin
authors.initials: S
authors.lastname: Katyal
authors.forename: Vanessa
authors.initials: V
authors.lastname: Enriquez-Rios
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Zhao
authors.forename: Helen R
authors.initials: HR
authors.lastname: Russell
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
mesh_terms: D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000196:embryology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism*; D049109:Cell Proliferation; D006651:Histocytochemistry; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008853:Microscopy; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D013234:Stem Cells / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases