The T3-induced gene KLF9 regulates oligodendrocyte differentiation and myelin regeneration.
The T3-induced gene KLF9 regulates oligodendrocyte differentiation and myelin regeneration.
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DOI：
10.1016/j.mcn.2012.03.007
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发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Barres BA
中科院分区：
文献类型：
--
作者：
Dugas JC;Ibrahim A;Barres BA
甲状腺功能减退症是一种被很好地描述的导致髓鞘退化的原因。此外，甲状腺激素（T3）最近在各种中枢神经系统脱髓鞘动物模型中被证明可以促进髓鞘再生。T3是如何促进健康髓磷脂的发育和再生的？为了开始理解T3驱动髓鞘形成的机制，我们已经确定了纯化少突胶质前体细胞（OPCs）中T3特异性调节的基因。通过基因组表达分析鉴定出4个转录因子，分别是kruppel样因子9 （KLF9）、碱性螺旋-环-螺旋家族成员e22 （BHLHe22）、Hairless （Hr）和Albumin D box-binding protein (DBP)，这些转录因子均可在短时间和长时间暴露于T3下诱导OPCs产生。为了开始研究这些基因在髓鞘形成中的作用，我们专注于这些基因中最快速和最强大的诱导，KLF9，并发现它是促进体外少突胶质细胞分化的必要和充分条件。令人惊讶的是，我们发现体内KLF9的缺失对发育过程中中枢神经系统髓鞘形成的影响可以忽略不计，但在铜酮诱导的脱髓鞘病变中，它会显著延缓髓鞘的再形成。这些实验表明KLF9可能是t3驱动的促进髓磷脂再生的信号级联的一个新的组成部分。未来对KLF9和其他已确定的t3诱导基因在髓鞘形成中的作用的分析可能会对如何在脱髓鞘疾病（如多发性硬化症）中增强髓鞘再生产生新的见解。
Hypothyroidism is a well-described cause of hypomyelination. In addition, thyroid hormone (T3) has recently been shown to enhance remyelination in various animal models of CNS demyelination. What are the ways in which T3 promotes the development and regeneration of healthy myelin? To begin to understand the mechanisms by which T3 drives myelination, we have identified genes regulated specifically by T3 in purified oligodendrocyte precursor cells (OPCs). Among the genes identified by genomic expression analyses were four transcription factors, Kruppel-like factor 9 (KLF9), basic helix-loop-helix family member e22 (BHLHe22), Hairless (Hr), and Albumin D box-binding protein (DBP), all of which were induced in OPCs by both brief and long term exposure to T3. To begin to investigate the role of these genes in myelination, we focused on the most rapidly and robustly induced of these, KLF9, and found it is both necessary and sufficient to promote oligodendrocyte differentiation in vitro. Surprisingly, we found that loss of KLF9 in vivo negligibly affects the formation of CNS myelin during development, but does significantly delay remyelination in cuprizone-induced demyelinated lesions. These experiments indicate that KLF9 is likely a novel integral component of the T3-driven signaling cascade that promotes the regeneration of lost myelin. Future analyses of the roles of KLF9 and other identified T3-induced genes in myelination may lead to novel insights into how to enhance the regeneration of myelin in demyelinating diseases such as multiple sclerosis.
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影响因子：
4.8
作者：
Furlow, JD;Kanamori, A
通讯作者：
Kanamori, A
DOI：
10.1016/s0165-3806(98)00081-9
发表时间：
1998-08-08
期刊：
DEVELOPMENTAL BRAIN RESEARCH
影响因子：
--
作者：
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通讯作者：
Kochupillai, N
影响因子：
4.8
作者：
Denver, RJ;Ouellet, L;Puymirat, J
通讯作者：
Puymirat, J
影响因子：
2.9
作者：
Ibarrola, N;RodriguezPena, A
通讯作者：
RodriguezPena, A
影响因子：
64.5
作者：
Emery B;Agalliu D;Cahoy JD;Watkins TA;Dugas JC;Mulinyawe SB;Ibrahim A;Ligon KL;Rowitch DH;Barres BA
通讯作者：
Barres BA