调节多巴胺和5-羟色胺在雄性秀丽线虫尾部ray表达机制的研究
摘要
多种因子协同调节不同的神经细胞,从而使它们分泌不同的神经递质,选择适当的轴突寻路(axon pathfinding),并形成各自特异的突触联结。研究调节产生各种类型和起源并具有一般或特殊表型的神经细胞的遗传网络是一个根本的课题,它有助于我们更好的掌握在各种机体中巧妙而复杂的神经网络。
终端神经细胞很重要的一个特性就是分泌不同的神经递质。常用的神经递质包括多巴胺(DA)和5-羟色胺(5-HT),它们控制多种的行为活动。多巴胺和5-羟色胺神经细胞的功能性异常可以导致精神和神经性紊乱[1]。例如,中脑的多巴胺神经细胞的选择性退化可引起帕金森综合症(Parkinson's disease),5-羟色胺神经细胞的功能异常和抑郁症(depression)的发生有直接的关系。选择不同的神经递质涉及到细胞内外多种因素的相互作用。例如,分泌信号分子Sonic hedgehog(Shh)和FGF8,具有活性的转录因子Lmx1b、Nurr1和Pitx3,对调节和维持中脑多巴胺神经细胞都是必需的。而后脑中5-羟色胺神经细胞需要胞外信号FGF4、Shh、FGF8,和Nkx2.2、Gata3和Pet1等胞内因子的协同作用[2,3]。然而,我们并不是十分清楚其他部位神经递质特异性表达的机制以及神经细胞其他特性如何被协同调节的。
雄性秀丽线虫ray神经细胞的发育提供了一个简单的模式体系,使我们更易于研究调节神经递质特异性表达以及对不同的发育阶段神经细胞的协同调节的机制[4]。每个从雄性尾部突出的手指型感觉器官ray,都包含两个结构型神经细胞的树突术端,其中一个A-型神经细胞(RnA)和一个B型神经细胞(RnB)。它们被包裹在一个神经胶质类结构细胞(Rnst)(n从1到9)中。不同ray各自的特性,包括形态,神经递质表达和轴突的轨迹。ray的A-型神经细胞包括R5A、R7A、R9A表达多巴胺神经递质:ray的B-型神经细胞包括R1B、R3B、R9B表达5-羟色胺神经递质。TGF-β信号通路和Hox基因egl-5(果蝇中Abd-B的同源物)对调节多巴胺和5-羟色胺神经细胞特异性起重要的作用[5,6]。TGF-β通路中组成成分的突变导致R5,R7,R9丧失表达多巴胺的特性,R9丧失表达5-羟色胺的特性。在egl-5突变体中,起源于侧线细胞(seam cell)V6(ray 2到6)的ray神经细胞不再表达多巴胺和5-羟色胺。鉴定调节多巴胺和5-羟色胺神经细胞的基因有助于我们了解在其他物种中神经递质特异性形成的分子机制。
在进化史上,多梳蛋白(PcG)扮演着转录水平上抑制Hox基因的重要角色,过去对此已经有很多研究[7]。在PcG突变体中,Hox基因异位表达,从而引起同源性异性转变(homeotic transformations)。PcG蛋白可通过对组蛋白尾部的修饰而形成抑制性染色质结构,这与它们在转录水平的抑制作用是一致的[8]。例如,ESC-E(Z)复合物含有一个可作用于组蛋白3(H3)的转甲基酶;PRC1复合物作为一个E3泛素连接酶作用于H2A;PhoRC具有结合甲基化H3K9和H4K20的活性[9,10]。PcG基因也调节非Hox基因的表达,其中包括调节发育和分化过程的因子,例如TGF-β和Wnt通路[11]。另外,脯乳动物ESC-E(Z)复合物,EED/EZH2作为转录抑制因子作用于肌动蛋白聚合和粘合素受体信号的转导[12,13]。PcG基因在调节神经细胞特异性中的作用还不清楚。
我们研究结果表明秀丽线虫PcG基因,sop-2和sor-3,参与调节神经递质的特异性表达和其他神经特性,包括轴突寻路。通过PcG基因调节神经细胞的特异性涉及到非-Hox靶基因。我们的研究揭示了通过表型基因遗传影响染色质结构进而调节神经细胞特异性的重要作用,这将有助于我们设计新的方案组建多巴胺神经细胞从而治疗包括帕金森综合症在内的多种人类神经退化性疾病。
Distinct neuronal fates, reflected by the production of appropriate neurotransmitter, selection of proper axon pathfinding, and formation of specific types of synaptic connectivity, are specified by the concerted action of many factors. Elucidation of the genetic circuitry that coordinately regulates the generation of these generic and specific phenotypes of neurons with different types and origins is a fundamental issue in understanding the formation of the exquisitely complex nerve circuits in various organisms.
One important feature of differentiated neurons is the distinct neurotransmitter produced. Common examples of neurotransmitters include dopamine (DA) and serotonin (5-HT), which control multiple behavior processes. Abnormal functioning of dopaminergic and serotonergic neurons cause mental and neurological disorders [1] . For example, selective degeneration of dopaminergic neurons in midbrain leads to Parkinson's disease, while abnormal function of 5-HT neurons has been implicated in depression. Selection of neurotransmitter phenotype involves the interactions of multiple extrinsic and intrinsic factors. For example, secreted signaling molecules Sonic hedgehog (Shh) and FGF8, and the activity of transcription factors Lmx1b, Nurr1, and Pitx3, are required for specification and maintenance of midbrain dopaminergic neurons, while 5HT neurons in the hindbrain are induced by the concerted action of extracellular signaling FGF4, Shh, FGF8, and intracellular factors, including Nkx2.2, Gata3, and Pet1 [2,3 ]. The mechanisms by which the neurotransmitters are specified in other regions and how the production of specific neurotransmitter is coordinately regulated with the development of other aspects of neuronal identities are largely unknown.
The development of C. elegans male ray neurons provides a simple system for exploring how distinct neurotransmitters are specified and how discrete developmental programs of neurons are coordinately regulated [4] . Each finger-like sensory ray, protruding in the mail tail, consists of the dendritic endings of two ultra-structurally distinct neurons, an A-type neuron (RnA) and an B-type neuron (RnB), wrapped in the process of a glial-like structural cell (Rnst) (where n stands for rays 1 to 9). Each ray has a unique identity due to the expression of distinct constellation of characteristics in their constituent cells: morphology, neurotransmitter choice, and axon trajectory. A subset of A-type neurons, R5A, R7A, and R9A, express the neurotransmitter dopamine, while a subset of B-type neurons, R1B, R3B, and R9B, express serotonin. We have shown previously that a TGF-βsignaling pathway and the Hox gene egl-5 (ortholog of Drosophila Abd-B) play important roles in the specification of dopaminergic and serotonergic ray neurons [5,6]. Mutations in components of TGF-βsignaling result in loss of dopamine expression in R5, 7, 9 and serotonin expression in R9. In the egl-5 mutant, dopaminergic and serotonergic fates are lost in rays derived from the epidermal seam cell V6 (rays 2 to 6), in which egl-5 is expressed. Identification of additional genes that specify dopaminergic and serotonergic neurons may contribute to our understanding of the molecular mechanisms underlying the formation of neurons with defined neurotransmitters in other organisms.
Polycomb group proteins (PcG) are most studied for their evolutionary roles in specifying positional identity through their transcriptional repression of Hox genes [7]. In PcG mutants, Hox genes are ectopically expressed, resulting in homeotic transformations. Consistent with their roles in transcriptional repression, PcG proteins mediate the formation of repressive chromatin structures by modifying the histone tails [8] . For example, the ESC-E(Z) complex contains a methyltransferase activity for histone 3 (H3), the PRC1 complex functions as an E3 ubiquitin ligase for H2A, and the PhoRC complex contains binding activity for methylated H3K9 and H4K20 [9,10] . PcG genes also regulate the expression of non-Hox genes, including factors involved in development and differentiation processes, such as TGF-βand Wnt [11] . In addition to acting as transcriptional repressors, the mammalian ESC/E(Z) PcG complex, EED/EZH2, functions in the cytoplasm in regulating actin polymerization and also in transducing an integrin receptor signal [12,13] . The roles of PcG genes in neuronal specification have yet to be determined.
In this study we demonstrated that the C. elegans PcG genes, sop-2 and sor-3, are involved in specifying neurotransmitter phenotype and several other neuronal properties, including axon pathfinding. Specification of certain neuronal identities by PcG genes involves regulation of non-Hox gene targets. Our studies revealed a key role of epigenetic regulation of chromatin structures in specifying neuronal fate and may contribute to the design of new strategies for engineering dopaminergic neurons for treating human diseases, such as Parkinson's disease.
终端神经细胞很重要的一个特性就是分泌不同的神经递质。常用的神经递质包括多巴胺(DA)和5-羟色胺(5-HT),它们控制多种的行为活动。多巴胺和5-羟色胺神经细胞的功能性异常可以导致精神和神经性紊乱[1]。例如,中脑的多巴胺神经细胞的选择性退化可引起帕金森综合症(Parkinson's disease),5-羟色胺神经细胞的功能异常和抑郁症(depression)的发生有直接的关系。选择不同的神经递质涉及到细胞内外多种因素的相互作用。例如,分泌信号分子Sonic hedgehog(Shh)和FGF8,具有活性的转录因子Lmx1b、Nurr1和Pitx3,对调节和维持中脑多巴胺神经细胞都是必需的。而后脑中5-羟色胺神经细胞需要胞外信号FGF4、Shh、FGF8,和Nkx2.2、Gata3和Pet1等胞内因子的协同作用[2,3]。然而,我们并不是十分清楚其他部位神经递质特异性表达的机制以及神经细胞其他特性如何被协同调节的。
雄性秀丽线虫ray神经细胞的发育提供了一个简单的模式体系,使我们更易于研究调节神经递质特异性表达以及对不同的发育阶段神经细胞的协同调节的机制[4]。每个从雄性尾部突出的手指型感觉器官ray,都包含两个结构型神经细胞的树突术端,其中一个A-型神经细胞(RnA)和一个B型神经细胞(RnB)。它们被包裹在一个神经胶质类结构细胞(Rnst)(n从1到9)中。不同ray各自的特性,包括形态,神经递质表达和轴突的轨迹。ray的A-型神经细胞包括R5A、R7A、R9A表达多巴胺神经递质:ray的B-型神经细胞包括R1B、R3B、R9B表达5-羟色胺神经递质。TGF-β信号通路和Hox基因egl-5(果蝇中Abd-B的同源物)对调节多巴胺和5-羟色胺神经细胞特异性起重要的作用[5,6]。TGF-β通路中组成成分的突变导致R5,R7,R9丧失表达多巴胺的特性,R9丧失表达5-羟色胺的特性。在egl-5突变体中,起源于侧线细胞(seam cell)V6(ray 2到6)的ray神经细胞不再表达多巴胺和5-羟色胺。鉴定调节多巴胺和5-羟色胺神经细胞的基因有助于我们了解在其他物种中神经递质特异性形成的分子机制。
在进化史上,多梳蛋白(PcG)扮演着转录水平上抑制Hox基因的重要角色,过去对此已经有很多研究[7]。在PcG突变体中,Hox基因异位表达,从而引起同源性异性转变(homeotic transformations)。PcG蛋白可通过对组蛋白尾部的修饰而形成抑制性染色质结构,这与它们在转录水平的抑制作用是一致的[8]。例如,ESC-E(Z)复合物含有一个可作用于组蛋白3(H3)的转甲基酶;PRC1复合物作为一个E3泛素连接酶作用于H2A;PhoRC具有结合甲基化H3K9和H4K20的活性[9,10]。PcG基因也调节非Hox基因的表达,其中包括调节发育和分化过程的因子,例如TGF-β和Wnt通路[11]。另外,脯乳动物ESC-E(Z)复合物,EED/EZH2作为转录抑制因子作用于肌动蛋白聚合和粘合素受体信号的转导[12,13]。PcG基因在调节神经细胞特异性中的作用还不清楚。
我们研究结果表明秀丽线虫PcG基因,sop-2和sor-3,参与调节神经递质的特异性表达和其他神经特性,包括轴突寻路。通过PcG基因调节神经细胞的特异性涉及到非-Hox靶基因。我们的研究揭示了通过表型基因遗传影响染色质结构进而调节神经细胞特异性的重要作用,这将有助于我们设计新的方案组建多巴胺神经细胞从而治疗包括帕金森综合症在内的多种人类神经退化性疾病。
Distinct neuronal fates, reflected by the production of appropriate neurotransmitter, selection of proper axon pathfinding, and formation of specific types of synaptic connectivity, are specified by the concerted action of many factors. Elucidation of the genetic circuitry that coordinately regulates the generation of these generic and specific phenotypes of neurons with different types and origins is a fundamental issue in understanding the formation of the exquisitely complex nerve circuits in various organisms.
One important feature of differentiated neurons is the distinct neurotransmitter produced. Common examples of neurotransmitters include dopamine (DA) and serotonin (5-HT), which control multiple behavior processes. Abnormal functioning of dopaminergic and serotonergic neurons cause mental and neurological disorders [1] . For example, selective degeneration of dopaminergic neurons in midbrain leads to Parkinson's disease, while abnormal function of 5-HT neurons has been implicated in depression. Selection of neurotransmitter phenotype involves the interactions of multiple extrinsic and intrinsic factors. For example, secreted signaling molecules Sonic hedgehog (Shh) and FGF8, and the activity of transcription factors Lmx1b, Nurr1, and Pitx3, are required for specification and maintenance of midbrain dopaminergic neurons, while 5HT neurons in the hindbrain are induced by the concerted action of extracellular signaling FGF4, Shh, FGF8, and intracellular factors, including Nkx2.2, Gata3, and Pet1 [2,3 ]. The mechanisms by which the neurotransmitters are specified in other regions and how the production of specific neurotransmitter is coordinately regulated with the development of other aspects of neuronal identities are largely unknown.
The development of C. elegans male ray neurons provides a simple system for exploring how distinct neurotransmitters are specified and how discrete developmental programs of neurons are coordinately regulated [4] . Each finger-like sensory ray, protruding in the mail tail, consists of the dendritic endings of two ultra-structurally distinct neurons, an A-type neuron (RnA) and an B-type neuron (RnB), wrapped in the process of a glial-like structural cell (Rnst) (where n stands for rays 1 to 9). Each ray has a unique identity due to the expression of distinct constellation of characteristics in their constituent cells: morphology, neurotransmitter choice, and axon trajectory. A subset of A-type neurons, R5A, R7A, and R9A, express the neurotransmitter dopamine, while a subset of B-type neurons, R1B, R3B, and R9B, express serotonin. We have shown previously that a TGF-βsignaling pathway and the Hox gene egl-5 (ortholog of Drosophila Abd-B) play important roles in the specification of dopaminergic and serotonergic ray neurons [5,6]. Mutations in components of TGF-βsignaling result in loss of dopamine expression in R5, 7, 9 and serotonin expression in R9. In the egl-5 mutant, dopaminergic and serotonergic fates are lost in rays derived from the epidermal seam cell V6 (rays 2 to 6), in which egl-5 is expressed. Identification of additional genes that specify dopaminergic and serotonergic neurons may contribute to our understanding of the molecular mechanisms underlying the formation of neurons with defined neurotransmitters in other organisms.
Polycomb group proteins (PcG) are most studied for their evolutionary roles in specifying positional identity through their transcriptional repression of Hox genes [7]. In PcG mutants, Hox genes are ectopically expressed, resulting in homeotic transformations. Consistent with their roles in transcriptional repression, PcG proteins mediate the formation of repressive chromatin structures by modifying the histone tails [8] . For example, the ESC-E(Z) complex contains a methyltransferase activity for histone 3 (H3), the PRC1 complex functions as an E3 ubiquitin ligase for H2A, and the PhoRC complex contains binding activity for methylated H3K9 and H4K20 [9,10] . PcG genes also regulate the expression of non-Hox genes, including factors involved in development and differentiation processes, such as TGF-βand Wnt [11] . In addition to acting as transcriptional repressors, the mammalian ESC/E(Z) PcG complex, EED/EZH2, functions in the cytoplasm in regulating actin polymerization and also in transducing an integrin receptor signal [12,13] . The roles of PcG genes in neuronal specification have yet to be determined.
In this study we demonstrated that the C. elegans PcG genes, sop-2 and sor-3, are involved in specifying neurotransmitter phenotype and several other neuronal properties, including axon pathfinding. Specification of certain neuronal identities by PcG genes involves regulation of non-Hox gene targets. Our studies revealed a key role of epigenetic regulation of chromatin structures in specifying neuronal fate and may contribute to the design of new strategies for engineering dopaminergic neurons for treating human diseases, such as Parkinson's disease.
引文
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66. Wang J, Lee CH, Lin S, and Lee T. (2006). Steroid hormone-dependent transformation of polyhomeotic mutant neurons in the Drosophila brain. Development 133, 1231-40.
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