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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs
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Fusion protein Isl1-Lhx3 specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs

机译：融合蛋白Isl1-Lhx3通过诱导运动神经元基因并伴随抑制中间神经元程序来确定运动神经元的命运

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摘要

Combinatorial transcription codes generate the myriad of cell types during development and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIM-complex mimicking fusion, induces a signature of MN tran-scriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM domain of Lhx3 are crucial for generating MNs without up-regulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of IsH and Lhx3 and the LIM domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog (Shh). RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of using embryonic transcription complexes for producing specific cell types from stem cells.
机译：组合转录代码在发育过程中产生了无数种细胞类型，因此可能为干细胞定向分化为特定细胞类型提供至关重要的见解。由Isl1和Lhx3组成的LIM复合体指导胚胎中脊髓运动神经元（MNs）的规范。在这里，我们报道Isl1-Lhx3，一种LIM复杂的模仿融合，诱导MN转录组的签名，并同时抑制神经元分化程序，从而作为干细胞中MNs的有效和特异性诱导剂。我们表明，等摩尔比的Isl1和Lhx3和Lhx3的LIM域对于产生MNs而不上调内部神经元基因至关重要。这些导致我们设计了Isl1-Lhx3，该结构保持了IsH和Lhx3的1：1比例以及Lhx3的LIM域。 Isl1-Lhx3在脊髓和胚胎干细胞中以高特异性和高效率驱动MN分化，从而绕过了对声波刺猬（Shh）的需求。 RNA-seq分析显示，Isl1-Lhx3诱导了一系列控制MNs功能方面的MN基因的表达，同时抑制了关键的中间神经元基因。我们的研究发现了一种用于定向MN生成和MN基因网络的高效方法。我们的结果也证明了使用胚胎转录复合物从干细胞生产特定细胞类型的一般策略。

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    Seunghee Lee; James M. Cuvillier; Bora Lee; Rongkun Shen; Jae W. Lee; Soo-Kyung Lee;

  • 作者单位

    Neuroscience Section, Department of Pediatrics, Pape Family Pediatric Research Institute,Vollum Institute, Oregon Health and Science University, Portland, OR 97239;

    Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030;

    Neuroscience Section, Department of Pediatrics, Pape Family Pediatric Research Institute;

    Neuroscience Section, Department of Pediatrics, Pape Family Pediatric Research Institute,Vollum Institute, Oregon Health and Science University, Portland, OR 97239;

    Neuroscience Section, Department of Pediatrics, Pape Family Pediatric Research Institute;

    Neuroscience Section, Department of Pediatrics, Pape Family Pediatric Research Institute,Vollum Institute, Oregon Health and Science University, Portland, OR 97239;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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