HIGH-FREQUENCY DEVELOPMENTAL ABNORMALITIES IN P53-DEFICIENT MICE
HIGH-FREQUENCY DEVELOPMENTAL ABNORMALITIES IN P53-DEFICIENT MICE
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DOI：
10.1016/s0960-9822(95)00183-7
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发表时间：
1995-08-01
期刊：
影响因子：
9.2
通讯作者：
CLARKE, AR
中科院分区：
文献类型：
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作者：
ARMSTRONG, JF;KAUFMAN, MH;CLARKE, AR
背景：已发展出几种携带肿瘤抑制基因P53零突变的小鼠。据报道，所有这些品系的纯合子小鼠在出生前发育正常，但随后迅速死于肿瘤。结果：在这里，我们报告了相当大比例的雌性P53(-/-)小鼠在胚胎发生期间或出生到断奶期间死亡，受到一系列异常的影响。在相当大比例(23%)的P53(-/-)女性胚胎中，神经管关闭的正常过程失败，导致脑外畸形和随后的无脑畸形。虽然这种现象主要与女性有关，但我们观察到一种影响男性胚胎的现象。除了一系列神经管缺陷外，这些胚胎中的许多还表现出一系列的颅面畸形，包括眼睛异常和上切牙牙齿形成缺陷。我们观察到P53(+/-)×P53(-/-)匹配的P53(-/-)雌性后代的数量显著减少，并且在对P53(-/-)×P53(+/+)匹配的P53(+/-)雌性后代的宫内分析中也观察到了显著减少。当雄性小鼠在交配前接受辐射时，其后代的畸形率显著增加，这与P53基因缺失有关。结论：我们发现与P53基因缺失相关的发育异常发生率很高。这表现为一系列的损害，主要是女性相关的神经管闭合缺陷。这些缺陷可能是因为P53在神经管关闭时发挥了生理作用，或者是因为P53缺失父母的单倍体配子内异常高的突变频率。
Background: Several strains of mice carrying null mutations of the tumour suppressor gene p53 have been developed. It has been reported that homozygous mice from all of these strains develop normally to birth, but then succumb rapidly to neoplasia.Results: Here, we report that a significant proportion of female p53(-/-) mice die during embryogenesis or in the period between birth and weaning, being subject to a spectrum of abnormalities. In a significant proportion (23%) of p53(-/-) female embryos, the normal process of neural tube closure failed, leading to exencephaly and subsequent anencephaly. Although this phenomenon was predominantly associated with females, we observed one affected male embryo. In addition to a spectrum of neural tube defects, many of these embryos exhibited a range of craniofacial malformations, including ocular abnormalities and defects in upper incisor tooth formation. We observed a significant reduction in the number of p53(-/-) female progeny of p53(+/-) x p53(-/-) matings, and also in an in utero analysis of the p53(+/-) female progeny of p53(-/-) x p53(+/+) matings. When male mice were exposed to irradiation prior to mating, a significant increase in the rate of abnormality was seen in the progeny, which was specifically associated with p53 deficiency.Conclusions: We have identified a high rate of developmental abnormalities associated with p53 deficiency. This manifests itself as a spectrum of lesions, predominantly female-associated defects in neural tube closure. These defects may arise either because p53 plays a physiological role at the time of neural tube closure, or because of an abnormally high frequency of mutation within the haploid gametes of p53-null parents.