Akt Regulates Sox10 Expression to Control Oligodendrocyte Differentiation via Phosphorylating FoxO1
Akt Regulates Sox10 Expression to Control Oligodendrocyte Differentiation via Phosphorylating FoxO1
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Akt 通过磷酸化 FoxO1 调节 Sox10 表达来控制少突胶质细胞分化
DOI：
10.1523/jneurosci.2432-20.2021
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发表时间：
2021-08
影响因子：
5.3
通讯作者：
Chen Guiquan
中科院分区：
文献类型：
--
作者：
Wang He;Liu Mengjia;Ye Zhuoyang;Zhou Cuihua;Bi Huiru;Wang Long;Zhang Chen;Fu Hui;Shen Ying;Yang Jian-Jun;Hu Yimin;Chen Guiquan
Sox10是一种众所周知的控制少突胶质细胞分化的因子，其表达受寡核苷酸2的调控。Akt作为一种重要的蛋白激酶，与脑白质异常的疾病密切相关。为了研究Akt是否以及如何调控OL的发育，我们建立了OL系细胞特异性Akt1/Akt2/AKT3三重条件敲除(Akt CTKO)小鼠。雄性和雌性小鼠均被使用。这些突变体在中枢神经系统中表现出成熟的OL的完全丧失和不变的细胞凋亡。我们发现Akt三种异构体的缺失导致Sox10的下调和大脑中磷酸化的FoxO1水平的降低。体外分析表明，Akt磷酸化位点突变的FoxO1的表达显著抑制了Sox10启动子的活性，这表明Akt对FoxO1的磷酸化对Sox10的表达是重要的。我们进一步证明了没有Akt磷酸化表位的突变体FoxO1富含Sox10启动子。总之，这项研究确定了Sox10表达和OL分化的一种新的FoxO1磷酸化依赖机制。意义陈述Akt的功能障碍与脑白质疾病有关，包括胼胝体发育不全。然而，Akt在少突胶质细胞分化中是否发挥重要作用尚不清楚。为了解决这个问题，我们产生了少突胶质细胞系特异性Akt1/Akt2/AKT3三条件基因敲除小鼠。AKT突变体表现出脑白质发育不足、成熟少突胶质细胞丢失、无髓鞘形成，以及中枢神经系统中凋亡细胞死亡的改变。我们证明了Akt三种异构体的缺失导致Sox10的下调，并且Akt对FoxO1的磷酸化是Sox10表达的关键。综上所述，这些发现揭示了一种调控Sox10表达的新机制。这项研究可能对蛋白激酶功能障碍引起的神经发育疾病的分子机制提供深入的认识。
Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation. SIGNIFICANCE STATEMENT Dysfunction of Akt is associated with white matter diseases including the agenesis of the corpus callosum. However, it remains unknown whether Akt plays an important role in oligodendrocyte differentiation. To address this question, we generated oligodendrocyte lineage cell-specific Akt1/Akt2/Akt3 triple-conditional knock-out mice. Akt mutants exhibit deficient white matter development, loss of mature oligodendrocytes, absence of myelination, and unchanged apoptotic cell death in the CNS. We demonstrate that deletion of Akt three isoforms leads to downregulation of Sox10, and that phosphorylation of FoxO1 by Akt is critical for Sox10 expression. Together, these findings reveal a novel mechanism to regulate Sox10 expression. This study may provide insights into molecular mechanisms for neurodevelopmental diseases caused by dysfunction of protein kinases.
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影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
影响因子：
5.3
作者：
Kuhlbrodt, K;Herbarth, B;Wegner, M
通讯作者：
Wegner, M
影响因子：
10.5
作者：
Stolt, CC;Rehberg, S;Wegner, M
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Wegner, M
影响因子：
16.2
作者：
Qinjie Weng;Ying Chen;Haibo Wang;Xiaomei Xu;Bo Yang;Qiaojun He;W. Shou;Yan Chen;Y. Higashi-Y.-Hi
通讯作者：
Qinjie Weng;Ying Chen;Haibo Wang;Xiaomei Xu;Bo Yang;Qiaojun He;W. Shou;Yan Chen;Y. Higashi-Y.-Hi
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A