Ministry of Education (MOE) Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing 210061, People's Republic of China.
Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou 213000, People's Republic of China.
J Neurosci. 2021 Sep 29;41(39):8163-8180. doi: 10.1523/JNEUROSCI.2432-20.2021. Epub 2021 Aug 12.
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 // triple conditional knock-out ( 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. analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the 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. 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 // 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.
Sox10 是一种众所周知的调控少突胶质细胞（OL）分化的因子，其表达受 Olig2 调控。Akt 作为一种重要的蛋白激酶，与白质异常相关疾病有关。为了研究 Akt 是否以及如何调控 OL 发育，我们生成了 OL 谱系细胞特异性 // 三重条件敲除（cTKO）小鼠。使用了雄性和雌性小鼠。这些突变体表现出成熟 OL 的完全缺失和中枢神经系统中未改变的凋亡细胞死亡。我们表明 Akt 三种同工型的缺失导致 Sox10 的下调和大脑中磷酸化 FoxO1 水平降低。分析表明，磷酸化位点突变的 FoxO1 的表达显著抑制 Sox10 启动子活性，表明 Akt 对 FoxO1 的磷酸化对于 Sox10 的表达很重要。我们进一步证明 Akt 磷酸化表位缺失的突变 FoxO1 在 Sox10 启动子中富集。总之，这项研究确定了 Sox10 表达和 OL 分化的一种新的 FoxO1 磷酸化依赖性机制。Akt 功能障碍与包括胼胝体发育不全在内的白质疾病有关。然而，Akt 是否在少突胶质细胞分化中发挥重要作用仍不清楚。为了解决这个问题，我们生成了 OL 谱系细胞特异性 // 三重条件敲除小鼠。Akt 突变体表现出白质发育缺陷、成熟少突胶质细胞缺失、髓鞘形成缺失和中枢神经系统中未改变的凋亡细胞死亡。我们表明 Akt 三种同工型的缺失导致 Sox10 的下调，Akt 对 FoxO1 的磷酸化对于 Sox10 的表达至关重要。总之，这些发现揭示了一种调节 Sox10 表达的新机制。这项研究可能为蛋白激酶功能障碍引起的神经发育疾病的分子机制提供新的见解。
