Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma
Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma
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DOI：
10.1101/gad.10.19.2411
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发表时间：
1996-10-01
影响因子：
10.5
通讯作者：
Baltimore, D
中科院分区：
文献类型：
--
作者：
Xu, Y;Ashley, T;Baltimore, D
ATM 是人类遗传性疾病共济失调毛细血管扩张症中突变的基因，是参与 DNA 代谢和细胞周期检查点控制的激酶家族的成员。为了帮助阐明 ATM 蛋白的生理作用，我们通过同源重组破坏了小鼠的 ATM 基因。对 ATM 敲除动物的初步评估表明，小鼠 ATM 基因的失活可重现共济失调毛细血管扩张的大部分表型。纯合突变体 (ATM(-/-)) 小鼠可存活、生长迟缓且不育。 ATM(-/-)小鼠的不育是由于减数分裂失败造成的。由于染色体突触异常和随后的染色体断裂，减数分裂在前期 I 的合子期/粗线期停止。 ATM(-/-)小鼠的免疫缺陷也很明显，包括B220(+)CD43(-)前B细胞、胸腺细胞和外周T细胞数量减少，以及T细胞依赖性免疫反应功能受损。 3至4个月时，ATM(-/-)小鼠的小脑组织学检查显示正常，并且小鼠没有明显的行为异常。大多数突变小鼠迅速发展为胸腺淋巴瘤并在 4 个月龄前死亡。这些发现表明，ATM 基因产物在多种细胞过程中发挥着重要作用，包括减数分裂、体细胞组织的正常生长、免疫发育和肿瘤抑制。
ATM, the gene mutated in the inherited human disease ataxia-telangiectasia, is a member of a family of kinases involved in DNA metabolism and cell-cycle checkpoint control. To help clarify the physiological roles of the ATM protein, we disrupted the ATM gene in mice through homologous recombination, Initial evaluation of the ATM knockout animals indicates that inactivation of the mouse ATM gene recreates much of the phenotype of ataxia-telangiectasia. The homozygous mutant (ATM(-/-)) mice are viable, growth-retarded, and infertile. The infertility of ATM(-/-) mice results from meiotic failure. Meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. Immune defects also are evident in ATM(-/-) mice, including reduced numbers of B220(+)CD43(-) pre-B cells, thymocytes, and peripheral T cells, as well as functional impairment of T-cell-dependent immune responses. The cerebella of ATM(-/-) mice appear normal by histologic examination at 3 to 4 months and the mice have no gross behavioral abnormalities. The majority of mutant mice rapidly develop thymic lymphomas and die before 4 months of age. These findings indicate that the ATM gene product plays an essential role in a diverse group of cellular processes, including meiosis, the normal growth of somatic tissues, immune development, and tumor suppression.