A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice
A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice
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DOI：
10.1073/pnas.151033798
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发表时间：
2001-07-17
影响因子：
11.1
通讯作者：
Hino, O
中科院分区：
文献类型：
--
作者：
Kobayashi, T;Minowa, O;Hino, O
结节性硬化症 (TS) 的特点是在多个器官中出现错构瘤，由 TSC1 或 TSC2 肿瘤抑制基因的种系突变引起。从 TS 患者症状的相似性来看，TSC1 和 TSC2 产物涉及共同途径。这里，为了分析Tsc1产品的功能，我们建立了一条Tsc？ （TSC1 同源物）通过基因打靶敲除小鼠。杂合Tsc1突变体（Tsc1（+/-））小鼠出现肾和肾外肿瘤，如肝血管瘤，在这些肿瘤中，野生型Tsc的丢失？观察到等位基因。纯合 Tsc1 突变体在胚胎 10.5-11.5 天左右死亡，通常与神经管未闭合有关。总体而言，Tsc1 敲除小鼠的表型与之前报道的 Tsc2 敲除小鼠的表型相似，这表明 Tsc1 和 Tsc2 产物的假定共同途径也可能存在于小鼠体内。然而值得注意的是，Tsc1(+/-)小鼠肾肿瘤的发展明显慢于Tsc2(+/-)小鼠。这里描述的 Tsc1 敲除小鼠将是阐明 Tsc1 和 Tsc2 产物的功能以及 TS 发病机制的有用模型。
Tuberous sclerosis (TS) is characterized by the development of hamartomas in various organs and is caused by a germ-line mutation in either TSC1 or TSC2 tumor suppressor genes, From the symptomatic resemblance among TS patients, involvement of TSC1 and TSC2 products in a common pathway has been suggested. Here, to analyze the function of the Tsc1 product, we established a line of Tsc? (TSC1 homologue) knockout mouse by gene targeting. Heterozygous Tsc1 mutant (Tsc1(+/-)) mice developed renal and extra-renal tumors such as hepatic hemangiomas, In these tumors, loss of wild-type Tsc? allele was observed. Homozygous Tsc1 mutants died around embryonic days 10.5-11.5, frequently associated with neural tube unclosure. As a whole, phenotypes of Tsc1 knockout mice resembled those of Tsc2 knockout mice previously reported, suggesting that the presumptive common pathway for Tsc1 and Tsc2 products may also exist in mice. Notably, however, development of renal tumors in Tsc1(+/-) mice was apparently slower than that in Tsc2(+/-) mice. The Tsc1 knockout mouse described here will be a useful model to elucidate the function of Tsc1 and Tsc2 products as well as pathogenesis of TS.