An essential function for NBS1 in the prevention of ataxia and cerebellar defects
An essential function for NBS1 in the prevention of ataxia and cerebellar defects
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DOI：
10.1038/nm1228
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发表时间：
2005-05-01
期刊：
影响因子：
82.9
通讯作者：
Wang, ZQ
中科院分区：
文献类型：
--
作者：
Frappart, PO;Tong, WM;Wang, ZQ
奈梅根断裂综合征(NBS)、共济失调毛细血管扩张症和共济失调毛细血管扩张症(ATLD)表现为重叠的表型，如生长迟缓、小头畸形、小脑发育缺陷和共济失调。然而，这些神经缺陷的分子发病机制仍然难以捉摸。在这里，我们发现在小鼠神经组织中NBN基因(也称为Nbs1)的失活导致NBS、共济失调毛细血管扩张症和ATLD的神经异常的组合，包括小头畸形、生长迟缓、小脑缺陷和共济失调。NBN的丢失会导致颗粒细胞前体细胞的增殖停滞和小脑有丝分裂后神经元的凋亡。此外，NBN缺陷的神经前体细胞表现出增殖缺陷(但不增加凋亡)，并含有更多的染色体断裂，伴随着共济失调毛细血管扩张突变蛋白(ATM)介导的P53激活。值得注意的是，P53的缺失实质上挽救了NBN突变小鼠的神经缺陷。本研究旨在探讨NBN基因产物NBS1的生理功能及DNA损伤反应在NBS、共济失调、毛细血管扩张症和ATLD神经系统异常中的作用。
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.