The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.
The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination.
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DOI：
10.1371/journal.pbio.1002467
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发表时间：
2016-05
期刊：
影响因子：
9.8
通讯作者：
John GR
中科院分区：
文献类型：
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作者：
Laitman BM;Asp L;Mariani JN;Zhang J;Liu J;Sawai S;Chapouly C;Horng S;Kramer EG;Mitiku N;Loo H;Burlant N;Pedre X;Hara Y;Nudelman G;Zaslavsky E;Lee YM;Braun DA;Lu QR;Narla G;Raine CS;Friedman SL;Casaccia P;John GR
gp 130家族的生长因子促进少突胶质细胞的分化、活力和髓鞘形成，但其作用机制尚不完全清楚。在这里，我们表明，这些影响是协调的，在一定程度上，由转录激活因子Krüppel样因子-6（Klf 6）。Klf 6在少突胶质祖细胞（OLP）中被gp 130因子快速诱导，并促进分化。相反，在具有谱系选择性Klf 6失活的小鼠中，OLP经历成熟停滞，随后是凋亡，并且CNS髓鞘形成失败。重叠的转录和染色质占有率分析将Klf 6置于新型gp 130-Klf-输入蛋白轴的连接处，该轴部分地通过控制核运输来促进分化和活力。Klf 6作为核输入因子importin-α5（Impα5）的gp 130敏感性反式激活因子，干扰该机制会中断逐步分化。强调了该轴在体内的重要性，gp 130信号传导条件性失活的小鼠显示出Klf 6和Impα5表达缺陷、OLP成熟停滞和凋亡以及CNS髓鞘形成失败。在中枢神经系统中白色物质的发育过程中，转录因子Klf 6协调gp 130-Stat 3信号传导的前髓鞘形成作用，并部分通过控制核运输促进少突胶质细胞分化。髓鞘是一种包围神经元轴突并促进神经冲动传递的膜状片，由中枢神经系统（CNS）中的少突胶质细胞和外周神经系统（PNS）中的许旺细胞形成。髓鞘形成失败或脱髓鞘会产生严重疾病的症状，如脑白质营养不良和多发性硬化症。这项研究确定了一种新的和必不可少的调节髓鞘形成的中枢神经系统：转录激活因子Krüppel样因子-6（Klf 6）。我们表明，Klf 6作为一个控制点，通过它的前髓鞘信号调节少突胶质细胞祖细胞的少突胶质细胞的发展。已知gp 130家族的生长因子通过激活转录因子Stat 3来促进少突胶质细胞的分化和存活，但它们如何做到这一点的机制细节仍不清楚。我们的研究结果表明Klf 6在少突胶质祖细胞中被gp 130生长因子诱导，并促进分化。此外，Klf 6失活的少突胶质细胞祖细胞不成熟，不能形成髓鞘，并最终死亡。我们还发现，在gp 130信号传导后，Klf 6激活核输入因子输入素-α5（Impα5），这是CNS中运输到核中的关键控制器。值得注意的是，Impα5的失活概括了Klf 6沉默的特征，而Impα5的表达可以部分挽救Klf 6缺陷型少突胶质细胞祖细胞的分化。最后，少突胶质细胞祖细胞中Stat 3的失活导致Klf 6和Impα5表达缺陷和髓鞘形成失败，与Klf 6失活产生的特征非常相似。总的来说，这些结果建立了gp 130-Stat 3信号传导和基于输入的核运输控制之间的联系，这对CNS中的髓鞘形成至关重要，并将Klf 6作为这些事件的关键协调者。
Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination. During the development of white matter in the central nervous system, the transcription factor Klf6 coordinates pro-myelinating effects of gp130-Stat3 signaling, and promotes oligodendrocyte differentiation in part via control of nuclear trafficking. Myelin, a membranous sheet that surrounds the axons of neurons and facilitates the transmission of nerve impulses, is formed by oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS). Failure to myelinate, or demyelination, produces the symptoms of serious diseases such as leukodystrophies and multiple sclerosis. This study identifies a novel and essential regulator of myelin formation in the CNS: the transcriptional activator Krüppel-like factor-6 (Klf6). We show that Klf6 acts as a control point through which pro-myelinating signals regulate the development of oligodendrocytes from oligodendrocyte progenitor cells. Growth factors of the gp130 family are known to promote differentiation and survival of oligodendrocytes, via activation of the transcription factor Stat3, but the mechanistic details of how they do it remain unclear. Our findings show that Klf6 is induced in oligodendrocyte progenitors by gp130 growth factors, and promotes differentiation. Furthermore, oligodendrocyte progenitor cells in which Klf6 is inactivated do not mature, fail to form myelin, and eventually die. We also uncover that upon gp130 signaling, Klf6 activates the nuclear import factor importin-α5 (Impα5), a key controller of trafficking into the nucleus in the CNS. Notably, inactivation of Impα5 recapitulates the features of silencing Klf6, whereas Impα5 expression can partially rescue differentiation in Klf6-deficient oligodendrocyte progenitors. Finally, inactivation of Stat3 in oligodendrocyte progenitors produces defective Klf6 and Impα5 expression and myelination failure, strongly resembling the features produced by Klf6 inactivation. Collectively, these results establish a connection between gp130-Stat3 signaling and importin-based control of nuclear trafficking, which is essential for myelination in the CNS, and places Klf6 as a key coordinator of these events.