An essential function for NBS1 in the prevention of ataxia and cerebellar defects.
Nijmegen breakage syndrome (NBS), ataxia telangiectasia and ataxia telangiectasia-like disorder (ATLD) show overlapping phenotypes such as growth retardation, microcephaly, cerebellar developmental defects and ataxia. However, the molecular pathogenesis of these neurological defects remains elusive. Here we show that inactivation of the Nbn gene (also known as Nbs1) in mouse neural tissues results in a combination of the neurological anomalies characteristic of NBS, ataxia telangiectasia and ATLD, including microcephaly, growth retardation, cerebellar defects and ataxia. Loss of Nbn causes proliferation arrest of granule cell progenitors and apoptosis of postmitotic neurons in the cerebellum. Furthermore, Nbn-deficient neuroprogenitors show proliferation defects (but not increased apoptosis) and contain more chromosomal breaks, which are accompanied by ataxia telangiectasia mutated protein (ATM)-mediated p53 activation. Notably, depletion of p53 substantially rescues the neurological defects of Nbn mutant mice. This study gives insight into the physiological function of NBS1 (the Nbn gene product) and the function of the DNA damage response in the neurological anomalies of NBS, ataxia telangiectasia and ATLD.
Frappart
Pierre-Olivier
PO
International Agency for Research on Cancer, Lyon, France.
Tong
Wei-Min
WM
Demuth
Ilja
I
Radovanovic
Ivan
I
Herceg
Zdenko
Z
Aguzzi
Adriano
A
Digweed
Martin
M
Wang
Zhao-Qi
ZQ
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001260:Ataxia Telangiectasia / Q000235:genetics* / Q000517:prevention & control; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D002531:Cerebellum / Q000473:pathology; D017931:DNA Primers; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D000076228:MRE11 Homologue Protein; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes