Deletion of the developmentallv essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss
Deletion of the developmentallv essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss
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DOI：
10.1016/j.stem.2007.03.002
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发表时间：
2007-07-01
期刊：
影响因子：
23.9
通讯作者：
Brown, Eric J.
中科院分区：
文献类型：
--
作者：
Ruzankina, Yaroslava;Pinzon-Guzman, Carolina;Brown, Eric J.
发育异常、癌症和过早衰老都与DNA损伤反应(DDR)缺陷有关。ATR检查点调节器的突变会导致小鼠(原肠发育前期致死性)和人类(塞克尔综合征)的发育缺陷。在这里，我们表明，在成年小鼠中消除ATR会导致组织稳态的缺陷，并迅速出现与年龄相关的表型，如头发灰白、脱发、后凸、骨质疏松症、胸腺退化、纤维化和其他异常。组织学和遗传学分析表明，ATR缺失会导致需要持续细胞增殖才能维持的组织中的急性细胞丢失。重要的是，ATR基因敲除小鼠的胸腺退化、脱发和头发变白与组织特异性干细胞和祖细胞的急剧减少以及组织更新和内环境平衡能力的耗尽有关。总而言之，这些研究表明，成年人由于缺失发育必需的DDR基因而导致的再生能力降低，足以导致与年龄相关的表型过早出现。
Developmental abnormalities, cancer, and premature aging each have been linked to defects in the DNA damage response (DDR). Mutations in the ATR checkpoint regulator cause developmental defects in mice (pregastrulation lethality) and humans (Seckel syndrome). Here we show that eliminating ATR in adult mice leads to defects in tissue homeostasis and the rapid appearance of age-related phenotypes, such as hair graying, alopecia, kyphosis, osteoporosis, thymic involution, fibrosis, and other abnormalities. Histological and genetic analyses indicate that ATR deletion causes acute cellular loss in tissues in which continuous cell proliferation is required for maintenance. Importantly, thymic involution, alopecia, and hair graying in ATR knockout mice were associated with dramatic reductions in tissue-specific stem and progenitor cells and exhaustion of tissue renewal and homeostatic capacity. In aggregate, these studies suggest that reduced regenerative capacity in adults via deletion of a developmentally essential DDR gene is sufficient to cause the premature appearance of age-related phenotypes.