PDF(Pubmed)
Abstract：
Mutations on γ-secretase subunits are associated with neurologic diseases. Whereas the role of γ-secretase in neurogenesis has been intensively studied, little is known about its role in astrogliogenesis. Recent evidence has demonstrated that astrocytes can be generated from oligodendrocyte precursor cells (OPCs). However, it is not well understood what mechanism may control OPCs to differentiate into astrocytes. To address the above questions, we generated two independent lines of oligodendrocyte lineage-specific presenilin enhancer 2 (Pen-2) conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by Olig1-Cre or NG2-CreERT2 causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in Pen-2 conditional KO mice. Mechanistic analysis reveals that deletion of Pen-2 inhibits the Notch signaling to upregulate signal transducer and activator of transcription 3, which triggers activation of GFAP to promote astrocyte differentiation. Together, these novel findings indicate that Pen-2 regulates the specification of astrocytes from OPCs through the signal transducer and activator of transcription 3 signaling.SIGNIFICANCE STATEMENT Astrocytes and oligodendrocyte (OLs) play critical roles in the brain. Recent evidence has demonstrated that astrocytes can be generated from OL precursor cells (OPCs). However, it remains poorly understood what mechanism governs the differentiation of OPCs into astrocytes. In this study, we took advantage of OL lineage cells specific presenilin enhancer 2 (Pen-2) conditional KO mice. We show that deletion of Pen-2 leads to dramatically enhanced astrocyte differentiation from OPCs in the CNS. Mechanistic analysis reveals that deletion of Pen-2 inhibits Hes1 and activates signal transducer and activator of transcription 3 to trigger GFAP activation which promotes astrocyte differentiation. Overall, this study identifies a novel function of Pen-2 in astrogliogenesis from OPCs.
摘要：
γ-分泌酶亚基的突变与神经系统疾病相关。而γ-分泌酶在神经发生中的作用已被深入研究,对其在星形胶质细胞生成中的作用知之甚少。最近的证据表明，星形胶质细胞可以从少突胶质细胞前体细胞（OPC）产生。然而,目前尚不清楚是什么机制可以控制OPCs分化为星形胶质细胞。为了解决上述问题，我们产生了两个独立的少突胶质细胞谱系特异性早老素增强子2（Pen-2）条件性KO小鼠系。使用雄性和雌性小鼠。在这里，我们证明了由Olig1-Cre或NG2-CreERT2介导的Pen-2的条件性失活导致星形胶质细胞的生成增强。谱系追踪实验表明，在Pen-2条件性KO小鼠中，异常产生的星形胶质细胞源自CNS中表达Cre的OPC。机制分析显示Pen-2的缺失抑制Notch信号传导以上调信号转导子和转录激活因子3,这触发GFAP的激活以促进星形胶质细胞分化。一起,这些新发现表明，Pen-2通过信号转导和转录激活因子3信号调节OPCs星形胶质细胞的规格。意义陈述星形胶质细胞和少突胶质细胞(OLs)在脑中起关键作用。最近的证据表明，星形胶质细胞可以从OL前体细胞（OPC）中产生。然而,目前尚不清楚OPCs分化为星形胶质细胞的机制是什么.在这项研究中,我们利用了OL谱系细胞特异性早老素增强子2（Pen-2）条件KO小鼠。我们表明，Pen-2的缺失导致CNS中OPCs的星形胶质细胞分化显着增强。机制分析显示Pen-2的缺失抑制Hes1并激活信号转导和转录激活因子3以触发促进星形胶质细胞分化的GFAP激活。总的来说,这项研究从OPCs中鉴定了Pen-2在星形胶质细胞生成中的新功能。
