mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells
mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells
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DOI：
10.1128/mcb.24.15.6710-6718.2004
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发表时间：
2004-08-01
影响因子：
5.3
通讯作者：
Yamanaka, S
中科院分区：
文献类型：
--
作者：
Murakami, M;Ichisaka, T;Yamanaka, S
TOR是一种丝氨酸-苏氨酸激酶，最初在酿酒酵母中被鉴定为雷帕霉素的靶标，然后发现在真核生物中高度保守。在黑腹果蝇中，TOR或其底物S6激酶的失活导致细胞大小减小和胚胎致死，表明TOR通路在细胞生长控制中的关键作用。然而，哺乳动物TOR（mTOR）的体内功能仍不清楚。在这项研究中，我们通过同源重组破坏了小鼠mTOR的激酶结构域。虽然杂合突变小鼠是正常的和可生育的，但纯合突变胚胎在植入后不久由于胚胎和胚外隔室中的细胞增殖受损而死亡。纯合子囊胚外观正常，但其内细胞团和滋养层在体外不能增殖。mTOR的C-末端六个氨基酸的缺失，这是激酶活性所必需的，导致胚胎干细胞的细胞大小减少和增殖停滞。这些数据表明，mTOR控制早期小鼠胚胎和胚胎干细胞的细胞大小和增殖。
TOR is a serine-threonine kinase that was originally identified as a target of rapamycin in Saccharomyces cerevisiae and then found to be highly conserved among eukaryotes. In Drosophila melanogaster, inactivation of TOR or its substrate, S6 kinase, results in reduced cell size and embryonic lethality, indicating a critical role for the TOR pathway in cell growth control. However, the in vivo functions of mammalian TOR (mTOR) remain unclear. In this study, we disrupted the kinase domain of mouse mTOR by homologous recombination. While heterozygous mutant mice were normal and fertile, homozygous mutant embryos died shortly after implantation due to impaired cell proliferation in both embryonic and extraembryonic compartments. Homozygous blastocysts looked normal, but their inner cell mass and trophoblast failed to proliferate in vitro. Deletion of the C-terminal six amino acids of mTOR, which are essential for kinase activity, resulted in reduced cell size and proliferation arrest in embryonic stem cells. These data show that mTOR controls both cell size and proliferation in early mouse embryos and embryonic stem cells.