State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, D-66421, Germany.
J Neurosci. 2021 Jun 9;41(23):4976-4990. doi: 10.1523/JNEUROSCI.2455-19.2021. Epub 2021 May 10.
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 () conditional KO mice. Both male and female mice were used. Here we demonstrate that conditional inactivation of Pen-2 mediated by or causes enhanced generation of astrocytes. Lineage-tracing experiments indicate that abnormally generated astrocytes are derived from Cre-expressing OPCs in the CNS in 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. 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.
γ-分泌酶亚基的突变与神经疾病有关。虽然 γ-分泌酶在神经发生中的作用已得到深入研究，但对其在星形胶质细胞发生中的作用知之甚少。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）中产生。然而，目前还不清楚是什么机制控制 OPC 分化为星形胶质细胞。为了解决上述问题，我们生成了两种独立的少突胶质细胞谱系特异性早老素增强子 2（Pen-2）条件性敲除（KO）小鼠品系。使用了雄性和雌性小鼠。在这里，我们证明了 Pen-2 的条件性失活由 Cre 表达的 OPC 介导，这会导致星形胶质细胞的过度生成。谱系追踪实验表明，在 条件性 KO 小鼠的中枢神经系统中，异常产生的星形胶质细胞来源于 Cre 表达的 OPC。机制分析表明，Pen-2 的缺失抑制 Notch 信号，上调信号转导和转录激活因子 3（STAT3），从而触发 GFAP 的激活，促进星形胶质细胞分化。总之，这些新发现表明 Pen-2 通过 STAT3 信号调节 OPC 向星形胶质细胞的特化。星形胶质细胞和少突胶质细胞（OLs）在大脑中发挥关键作用。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，目前仍不清楚是什么机制控制 OPC 分化为星形胶质细胞。在这项研究中，我们利用 OL 谱系细胞特异性早老素增强子 2（Pen-2）条件性 KO 小鼠。我们发现 Pen-2 的缺失导致中枢神经系统 OPC 中星形胶质细胞的分化明显增强。机制分析表明，Pen-2 的缺失抑制 Hes1 并激活信号转导和转录激活因子 3，触发 GFAP 激活，促进星形胶质细胞分化。总的来说，这项研究确定了 Pen-2 在 OPC 向星形胶质细胞分化中的新功能。
