AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development.
AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development.
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DOI：
10.1016/j.devcel.2009.01.005
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发表时间：
2009-02
影响因子：
11.8
通讯作者：
Milbrandt, Jeffrey
中科院分区：
文献类型：
--
作者：
Dasgupta, Biplab;Milbrandt, Jeffrey
AMP激活的蛋白激酶(AMPK)是一种进化保守的代谢感受器，它对细胞能量水平的变化做出反应，以维持能量平衡。虽然它在代谢动态平衡中的作用已经有了很好的文献记载，但它在哺乳动物发育中的作用还不是很清楚。在这里，我们证明了缺乏调节AMPKβ1亚单位的突变小鼠有严重的脑部异常。β-1−/−小鼠表现为齿状回和小脑萎缩，神经元、少突胶质细胞和整个中枢神经系统髓鞘形成严重丧失。这些异常源于AMPK活性降低，继而导致神经干细胞和祖细胞(NPC)的细胞周期缺陷。β1−/−缺失是由于视网膜母细胞瘤蛋白(Rb)的低磷酸化所致，Rb在Ser804位被AMPK直接磷酸化。生长因子和能量限制都利用AMPK-Rb轴促进鼻咽癌生长。综上所述，我们的结果表明，代谢传感器AMPK整合了生长因子信号和细胞周期控制来调节大脑发育。
AMP activated protein kinase (AMPK) is an evolutionary conserved metabolic sensor that responds to alterations in cellular energy levels to maintain energy balance. While its role in metabolic homeostasis is well documented, its role in mammalian development is less clear. Here we demonstrate that mutant mice lacking the regulatory AMPK β1 subunit have profound brain abnormalities. The β1−/− mice show atrophy of the dentate gyrus and cerebellum, severe loss of neurons, oligodendrocytes and myelination throughout the CNS. These abnormalities stem from reduced AMPK activity with ensuing cell cycle defects in neural stem and progenitor cells (NPC). The β1−/− NPC deficits result from hypophosphorylation of the retinoblastoma protein (Rb), which is directly phosphorylated by AMPK at Ser804. The AMPK-Rb axis is utilized by both growth factors and energy restriction to increase NPC growth. Together, our results reveal that the metabolic sensor AMPK integrates growth factor signaling with cell cycle control to regulate brain development.
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