The Evolutionarily Conserved LIM Homeodomain Protein LIM-4/LHX6 Specifies the Terminal Identity of a Cholinergic and Peptidergic C. elegans Sensory/Inter/Motor Neuron-Type.
The Evolutionarily Conserved LIM Homeodomain Protein LIM-4/LHX6 Specifies the Terminal Identity of a Cholinergic and Peptidergic C. elegans Sensory/Inter/Motor Neuron-Type.
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DOI：
10.1371/journal.pgen.1005480
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发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
Kim K
中科院分区：
文献类型：
--
作者：
Kim J;Yeon J;Choi SK;Huh YH;Fang Z;Park SJ;Kim MO;Ryoo ZY;Kang K;Kweon HS;Jeon WB;Li C;Kim K
特异性转录因子的表达决定了有丝分裂后神经元的分化特征。然而，特定分子决定神经细胞命运的机制以及转录因子在进化过程中功能的保守程度尚不完全清楚。在线虫中，胆碱能和多肽能的SMB感觉/间/运动神经元支配头部的肌肉象限，并控制正弦运动的振幅。我们发现LIM同源盒蛋白LIM-4决定了SMB神经元的神经元特征。在lim-4突变动物中，末端分化基因，如胆碱能基因电池和flp-12神经肽基因的表达被完全取消，因此SMB神经元的功能受到损害。LIM-4活性通过一个独特的顺式调控基序直接调节SMB标记基因的表达，从而促进SMB的鉴定。两个人类LIM-4同源物LHX6和LHX8在秀丽隐杆线虫中功能替代LIM-4。此外，秀丽隐杆线虫LIM-4或人LHX6可以诱导人神经细胞系的胆碱能和肽能特性。我们的研究结果表明，进化上保守的LIM-4/LHX6同源结构域蛋白在精确的神经元亚型的产生中起作用。神经系统的正确生成和维护对动物的生命至关重要。这些过程的失调会导致多种神经发育障碍。不仅要确定决定神经细胞命运的发育机制，而且要了解这些机制在进化上的保守程度，这是一项艰巨的挑战。在这里，我们描述了一种发育机制，该机制决定了秀丽隐杆线虫中特定胆碱能和多肽能神经元类型的命运。我们发现LIM -4 LIM同源结构域转录因子通过结合独特的DNA序列来促进和维持特定的胆碱能和肽能特性和功能是必要和充分的。我们还证明秀丽隐杆线虫lim-4和人类LHX6具有惊人的功能相似性；具体来说，秀丽隐杆线虫LIM-4或人LHX6可以诱导人神经细胞系的胆碱能和肽能特性。鉴于这些转录因子的高度保守性，这些发育机制可能也普遍适用于其他生物的神经系统。
The expression of specific transcription factors determines the differentiated features of postmitotic neurons. However, the mechanism by which specific molecules determine neuronal cell fate and the extent to which the functions of transcription factors are conserved in evolution are not fully understood. In C. elegans, the cholinergic and peptidergic SMB sensory/inter/motor neurons innervate muscle quadrants in the head and control the amplitude of sinusoidal movement. Here we show that the LIM homeobox protein LIM-4 determines neuronal characteristics of the SMB neurons. In lim-4 mutant animals, expression of terminal differentiation genes, such as the cholinergic gene battery and the flp-12 neuropeptide gene, is completely abolished and thus the function of the SMB neurons is compromised. LIM-4 activity promotes SMB identity by directly regulating the expression of the SMB marker genes via a distinct cis-regulatory motif. Two human LIM-4 orthologs, LHX6 and LHX8, functionally substitute for LIM-4 in C. elegans. Furthermore, C. elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in the human neuronal cell lines. Our results indicate that the evolutionarily conserved LIM-4/LHX6 homeodomain proteins function in generation of precise neuronal subtypes. The correct generation and maintenance of the nervous system is critical for the animal’s life. Dysregulation of these processes leads to multiple neurodevelopmental disorders. It has been a daunting challenge not only to identify the developmental mechanisms that determine neuronal cell fate, but also to understand the extent to which the mechanisms are evolutionarily conserved. Here, we describe a developmental mechanism that determines the fate of a specific cholinergic and peptidergic neuronal type in C. elegans. We show that the lim-4 LIM homeodomain transcription factor is necessary and sufficient to promote and maintain the specific cholinergic and peptidergic properties and functions via binding to unique DNA sequences. We also demonstrate that C. elegans lim-4 and human LHX6 show striking functional similarity; specifically, C. elegans LIM-4 or human LHX6 can induce cholinergic and peptidergic characteristics in human neuronal cell lines. Given the high conservation of these transcription factors, these developmental mechanisms are likely to be generally applicable in the nervous system of other organisms as well.