Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom's syndrome gene
Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom's syndrome gene
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DOI：
10.1101/gad.12.21.3382
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发表时间：
1998-11-01
影响因子：
10.5
通讯作者：
Leder, P
中科院分区：
文献类型：
--
作者：
Chester, N;Kuo, F;Leder, P
Bloom综合征是一种常染色体遗传病，其特征是在细胞水平上表现为基因组不稳定和姐妹染色体互换（SCE）增加。该疾病的临床特征包括比例性侏儒症和易患多种恶性肿瘤。人BLM基因最近已被克隆，并编码DNA解旋酶。小鼠布卢姆氏综合征基因（Blm）中靶向突变的纯合子小鼠胚胎发育延迟，并在胚胎第13.5天死亡。中断基因是人BLM基因的同源物的事实通过其同源序列、其染色体位置以及通过在培养的鼠Blm（-/-）成纤维细胞中显示高数目的SCE来证实。在人类中观察到的比例性侏儒症与小鼠Blm（-/-）胚胎在妊娠中期观察到的小尺寸和发育延迟（12-24小时）一致。有趣的是，突变胚胎的生长迟缓可以解释为一波增加的细胞凋亡的外胚层限制早期植入后胚胎发生。突变胚胎不能存活超过13.5天，此时表现出严重的贫血。Blm（-/-）胚胎的红细胞及其前体细胞在外观上是异质的，并且具有增加的巨细胞和微核数量。红细胞中的凋亡波和微核的出现都可能是由复制或分离染色体引起的DNA损伤的细胞后果。
Bloom's syndrome is a human autosomal genetic disorder characterized at the cellular level by genome instability and increased sister chomatid exchanges (SCEs). Clinical features of the disease include proportional dwarfism and a predisposition to develop a wide variety of malignancies. The human BLM gene has been cloned recently and encodes a DNA helicase. Mouse embryos homozygous for a targeted mutation in the murine Bloom's syndrome gene (Blm) are developmentally delayed and die by embryonic day 13.5. The fact that the interrupted gene is the homolog of the human BLM gene was confirmed by its homologous sequence, its chromosomal location, and by demonstrating high numbers of SCEs in cultured murine Blm(-/-) fibroblasts. The proportional dwarfism seen in the human is consistent with the small size and developmental delay (12-24 hr) seen during mid-gestation in murine Blm(-/-) embryos. Interestingly, the growth retardation in mutant embryos can be accounted for by a wave of increased apoptosis in the epiblast restricted to early post-implantation embryogenesis. Mutant embryos do not survive past day 13.5, and at this time exhibit severe anemia. Red blood cells and their precursors from Blm(-/-) embryos are heterogeneous in appearance and have increased numbers of macrocytes and micronuclei. Both the apoptotic wave and the appearance of micronuclei in red blood cells are likely cellular consequences of damaged DNA caused by effects an replicating or segregating chromosomes.