Nbn and atm cooperate in a tissue and developmental stage-specific manner to prevent double strand breaks and apoptosis in developing brain and eye.
Nibrin (NBN or NBS1) and ATM are key factors for DNA Double Strand Break (DSB) signaling and repair. Mutations in NBN or ATM result in Nijmegen Breakage Syndrome and Ataxia telangiectasia. These syndromes share common features such as radiosensitivity, neurological developmental defects and cancer predisposition. However, the functional synergy of Nbn and Atm in different tissues and developmental stages is not yet understood. Here, we show in vivo consequences of conditional inactivation of both genes in neural stem/progenitor cells using Nestin-Cre mice. Genetic inactivation of Atm in the central nervous system of Nbn-deficient mice led to reduced life span and increased DSBs, resulting in increased apoptosis during neural development. Surprisingly, the increase of DSBs and apoptosis was found only in few tissues including cerebellum, ganglionic eminences and lens. In sharp contrast, we showed that apoptosis associated with Nbn deletion was prevented by simultaneous inactivation of Atm in developing retina. Therefore, we propose that Nbn and Atm collaborate to prevent DSB accumulation and apoptosis during development in a tissue- and developmental stage-specific manner.
Programa de Biologia Celular e do Desenvolvimento, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Paulo M G
PM
Rodrigues
Paulius
P
Grigaravicius
Martina
M
Remus
Gabriel R
GR
Cavalheiro
Anielle L
AL
Gomes
Maurício
M
Rocha-Martins
Mauricio R
MR
Martins
Lucien
L
Frappart
David
D
Reuss
Peter J
PJ
McKinnon
Andreas
A
von Deimling
Rodrigo A P
RA
Martins
Pierre-Olivier
PO
Frappart
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins; D004843:Epistasis, Genetic; D005123:Eye / Q000196:embryology / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics*; D010641:Phenotype; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D064007:Ataxia Telangiectasia Mutated Proteins