A Foxo/Notch pathway controls myogenic differentiation and fiber type specification
A Foxo/Notch pathway controls myogenic differentiation and fiber type specification
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DOI：
10.1172/jci32054
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发表时间：
2007-09-01
影响因子：
15.9
通讯作者：
Accili, Domenico
中科院分区：
文献类型：
--
作者：
Kitamura, Tadahiro;Kitamura, Yukari Ido;Accili, Domenico
叉头盒O(FOXO)转录因子调控新陈代谢和细胞分化。与FOXO依赖的代谢途径和靶基因不同，这些蛋白质调节分化的机制尚未被探索。Notch信号的激活模拟了FOXO功能获得对细胞分化的影响。以肌肉分化为模型系统，我们证明FOXO通过促进Notch效应器CSL的辅阻遏子清除，从而激活Notch靶基因，从而在物理和功能上与Notch相互作用。固有活性Foxo1对成肌细胞分化的抑制可以通过抑制Notch信号而部分挽救，而Foxo1功能的丧失则排除了Notch对肌肉发生的抑制，并增加了成肌决定基因(MyoD)的表达。因此，在骨骼肌中，有条件的Foxo1消融导致含有MyoD的(快抽动)肌纤维的形成增加，以含有肌生成素的(慢抽动)纤维为代价，改变了纤维类型的分布。Notch/Foxo1的合作可能通过Notch整合环境信号和通过Foxo1调节代谢信号，从而调节祖细胞的维持和分化。
Forkhead box O (Foxo) transcription factors govern metabolism and cellular differentiation. Unlike Foxo-dependent metabolic pathways and target genes, the mechanisms by which these proteins regulate differentiation have not been explored. Activation of Notch signaling mimics the effects of Foxo gain of function on cellular differentiation. Using muscle differentiation as a model system, we show that Foxo physically and functionally interacts with Notch by promoting corepressor clearance from the Notch effector Csl, leading to activation of Notch target genes. Inhibition of myoblast differentiation by constitutively active Foxo1 is partly rescued by inhibition of Notch signaling while Foxo1 loss of function precludes Notch inhibition of myogenesis and increases myogenic determination gene (MyoD) expression. Accordingly, conditional Foxo1 ablation in skeletal muscle results in increased formation of MyoD-containing (fast-twitch) muscle fibers and altered fiber type distribution at the expense of myogenin-containing (slow-twitch) fibers. Notch/Foxo1 cooperation may integrate environmental cues through Notch with metabolic cues through Foxo1 to regulate progenitor cell maintenance and differentiation.