Disease states associated with telomerase deficiency appear earlier in mice with short telomeres
Disease states associated with telomerase deficiency appear earlier in mice with short telomeres
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DOI：
10.1093/emboj/18.11.2950
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发表时间：
1999-06-01
期刊：
影响因子：
11.4
通讯作者：
Blasco, MA
中科院分区：
文献类型：
--
作者：
Herrera, E;Samper, E;Blasco, MA
小鼠端粒酶RNA（mTR（-/-））缺陷和缺乏端粒酶活性的小鼠只能繁殖大约六代，这是由于雄性和雌性生育力降低以及与神经管闭合缺陷相关的胚胎致死率增加。尽管晚代mTR（-/-）小鼠显示出造血系统缺陷，但它们能存活至成年，仅在老年时显示出存活力降低，为了评估遗传背景对端粒酶缺陷对生存力的影响的贡献，我们在C57 BL 6背景上产生了mTR（-/-）突变体，其显示出比原始混合遗传背景C57 BL 6/129 Sv更短的端粒。有趣的是，这些小鼠只能繁殖四代，与野生型小鼠相比，晚代mTR（-/-）小鼠的存活率随着年龄的增长而急剧下降。第4代小鼠中的50%仅在5个月大时死亡。在晚代小鼠中，这种随年龄增长而降低的生存力与端粒缩短、不育、脾萎缩、B和T细胞增殖能力降低、血液学异常和小肠萎缩一致。这些结果表明，mTR（-/-）小鼠中的端粒缩短导致生物体生存力的进行性丧失。
Mice deficient for the mouse telomerase RNA (mTR(-/-)) and lacking telomerase activity can only be bred for approximately six generations due to decreased male and female fertility and to an increased embryonic lethality associated with a neural tube closure defect, Although late generation mTR(-/-) mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age, To assess the contribution of genetic background to the effect of telomerase deficiency on viability, we generated mTR(-/-) mutants on a C57BL6 background, which showed shorter telomeres than the original mixed genetic background C57BL6/129Sv. Interestingly, these mice could be bred for only four generations and the survival of late generation mTR(-/-) mice decreased dramatically with age as compared with their wild-type counterparts. Fifty percent of the generation 4 mice die at only 5 months of age, This decreased viability with age in the late generation mice is coincident with telomere shortening, sterility, splenic atrophy, reduced proliferative capacity of B and T cells, abnormal hematology and atrophy of the small intestine, These results indicate that telomere shortening in mTR(-/-) mice leads to progressive loss of organismal viability.