Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone developement, and impeded adipogenesis in mice lacking Akt1 and Akt2
Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone developement, and impeded adipogenesis in mice lacking Akt1 and Akt2
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DOI：
10.1101/gad.1089403
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发表时间：
2003-06-01
影响因子：
10.5
通讯作者：
Hay, N
中科院分区：
文献类型：
--
作者：
Peng, XD;Xu, PZ;Hay, N
为了阐明丝氨酸/苏氨酸激酶Akt/PKB在体内的功能，我们产生了缺乏akt 1和akt 2基因的小鼠。Akt 1/Akt 2双敲除（DKO）小鼠表现出严重的生长缺陷，并在出生后不久死亡。这些小鼠表现出由于增殖缺陷导致的皮肤发育受损、由于个体肌细胞大小显著减小导致的严重骨骼肌萎缩以及骨发育受损。这些缺陷与IGF-1受体缺陷小鼠的表型惊人相似，表明Akt可能是发育过程中IGF-1受体最关键的下游效应子。此外，Akt 1/Akt 2 DKO小鼠表现出脂肪生成受阻。具体而言，Akt 1和Akt 2是诱导PPARgamma表达所必需的，PPARgamma是脂肪形成的主要调节因子，从而确立了Akt在脂肪细胞分化中的新的重要作用。总之，Akt 1和Akt 2的组合缺失确立了Akt在细胞增殖、生长和分化中的体内作用。尽管在Akt 1/Akt 2 DKO细胞中观察到Akt 3介导的Akt活性水平较低，但Akt的这些功能未被发现，这表明维持正常细胞增殖、生长和分化需要Akt活性的临界阈值水平。
To elucidate the functions of the serine/threonine kinase Akt/PKB in vivo, we generated mice lacking both akt1 and akt2 genes. Akt1/Akt2 double-knockout (DKO) mice exhibit severe growth deficiency and die shortly after birth. These mice display impaired skin development because of a proliferation defect, severe skeletal muscle atrophy because of a marked decrease in individual muscle cell size, and impaired bone development. These defects are strikingly similar to the phenotypes of IGF-1 receptor-deficient mice and suggest that Akt may serve as the most critical downstream effector of the IGF-1 receptor during development. In addition, Akt1/Akt2 DKO mice display impeded adipogenesis. Specifically, Akt1 and Akt2 are required for the induced expression of PPARgamma, the master regulator of adipogenesis, establishing a new essential role for Akt in adipocyte differentiation. Overall, the combined deletion of Akt1 and Akt2 establishes in vivo roles for Akt in cell proliferation, growth, and differentiation. These functions of Akt were uncovered despite the observed lower level of Akt activity mediated by Akt3 in Akt1/Akt2 DKO cells, suggesting that a critical threshold level of Akt activity is required to maintain normal cell proliferation, growth, and differentiation.