Functional Diversification of Motor Neuron-specific Isl1 Enhancers during Evolution
Functional Diversification of Motor Neuron-specific Isl1 Enhancers during Evolution
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DOI：
10.1371/journal.pgen.1005560
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发表时间：
2015-10-01
期刊：
影响因子：
4.5
通讯作者：
Song, Mi-Ryoung
中科院分区：
文献类型：
--
作者：
Kim, Namhee;Park, Chungoo;Song, Mi-Ryoung
运动神经元的功能多样化已经发生，以便选择性地控制包括头部、躯干和四肢的不同身体部位的运动。在这里，我们报告说，转录的Isl 1，运动神经元的身份所必需的主要基因，是由两个增强子，CREST 1（E1）和CREST 2（E2），允许选择性基因表达的Isl 1运动神经元。将GFP报告基因导入鸡神经管显示，E1在后脑运动神经元和脊髓运动神经元中是活跃的，而E2在控制肢体肌肉的脊髓外侧运动柱（LMC）中是活跃的。全基因组ChIP-Seq分析结合报告基因分析表明，Phox 2和Isl 1-Lhx 3复合物与E1结合，并分别驱动Isl 1的后脑和脊髓特异性表达。有趣的是，Lhx 3单独足以激活E1，这可能有助于启动Isl 1表达时，祖细胞刚刚发展成运动神经元。E2由允许Isl 1在LMCm神经元中表达的onecut 1（OC-1）因子诱导。有趣的是，E1的核心区域在进化中一直是保守的，即使在七鳃鳗中也是如此，七鳃鳗是一种具有原始运动神经元的无颌脊椎动物。从七鳃鳗到小鼠的所有E1序列对Phox 2a和Isl 1-Lhx 3复合物的反应同样良好。相反，E2，肢体支配运动神经元的增强子，只在四足动物中发现。这表明进化上保守的增强子允许运动神经元的多样化。
Functional diversification of motor neurons has occurred in order to selectively control the movements of different body parts including head, trunk and limbs. Here we report that transcription of Isl1, a major gene necessary for motor neuron identity, is controlled by two enhancers, CREST1 (E1) and CREST2 (E2) that allow selective gene expression of Isl1 in motor neurons. Introduction of GFP reporters into the chick neural tube revealed that E1 is active in hindbrain motor neurons and spinal cord motor neurons, whereas E2 is active in the lateral motor column (LMC) of the spinal cord, which controls the limb muscles. Genome-wide ChIP-Seq analysis combined with reporter assays showed that Phox2 and the Isl1-Lhx3 complex bind to E1 and drive hindbrain and spinal cord-specific expression of Isl1, respectively. Interestingly, Lhx3 alone was sufficient to activate E1, and this may contribute to the initiation of Isl1 expression when progenitors have just developed into motor neurons. E2 was induced by onecut 1 (OC-1) factor that permits Isl1 expression in LMCm neurons. Interestingly, the core region of E1 has been conserved in evolution, even in the lamprey, a jawless vertebrate with primitive motor neurons. All E1 sequences from lamprey to mouse responded equally well to Phox2a and the Isl1-Lhx3 complex. Conversely, E2, the enhancer for limb-innervating motor neurons, was only found in tetrapod animals. This suggests that evolutionarily-conserved enhancers permit the diversification of motor neurons.