对小鼠SUN蛋白（SUN1、SUN2）和KASH蛋白（Syne-1、Syne-2）在骨骼肌细胞核锚定、大脑神经细胞迁移、视网膜发育、以及DNA损伤反应中的功能研究
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摘要
细胞核在细胞中的迁移和锚定是一种广泛存在的细胞学现象,它参与多种生物学过程,对于生物体的生长发育和疾病发生至关重要。经过多年的研究,科学家们发现细胞微管和微丝骨架系统参与调控细胞核的迁移和锚定,但是并不清楚细胞骨架究竟如何连接到细胞核膜上。通过遗传学方法,科学家们在酵母、线虫、果蝇等模式生物中发现了SUN蛋白和KASH蛋白这两类细胞核膜蛋白,它们分别定位在内核膜和外核膜上,对于细胞核的迁移和锚定至关重要。哺乳动物中也存在SUN蛋白和KASH蛋白家族同源蛋白,对于这两类蛋白在哺乳动物细胞核迁移和锚定中的功能,以及它们对于哺乳动物发育的重要性还有待进一步的研究。本论文中,我们利用SUN蛋白SUN1、SUN2和KASH蛋白Syne-1/Nesprin-1、Syne-2/Nesprin-2基因敲除小鼠,研究了这四种蛋白在小鼠骨骼肌细胞核锚定、大脑神经细胞发生和迁移、光感受细胞的发生和细胞核迁移、以及DNA损伤修复过程中的功能。
哺乳动物的骨骼肌细胞是由上百个肌原细胞融合而成的合胞体,每个细胞中有上百个细胞核按一定间距分布在细胞膜下表面,这些细胞核被称为非突触下细胞核,另有3-8个细胞核锚定在骨骼肌神经肌肉接头下,被称为突触下细胞核。我们提出的问题是SUN蛋白和KASH蛋白是否决定这些细胞核在细胞中的精确定位。我们以前的研究发现KASH蛋白Syne-1/Nesprin-1对于小鼠骨骼肌突触下细胞核和非突触下细胞核的锚定都必不可少,但还不知道SUN蛋白是否也参与这些过程。如本论文第二章所述,我和张晓昌博士合作发现仅缺失Sun1基因导致突触下细胞核的锚定被部分破坏,缺失Sun1和Sun2基因的3个甚至4个等位基因后,突触下细胞核的锚定缺陷更加严重,这说明SUN1和SUN2对于突触下细胞核的锚定有剂量效应。我进一步发现在Sun1Sun2双敲除骨骼肌细胞中,非突触下细胞核的锚定被破坏,Syne-1也不能定位在核膜上。这些结果说明在骨骼肌细胞核的锚定中,SUN1和SUN2通过定位Syne-1到核膜上,从而连接细胞核与细胞骨架,调节细胞核在骨骼肌细胞中的定位。
哺乳动物大脑发育伴随有大量的神经细胞发生和迁移,细胞核的移动对于这两个过程都至关重要。研究发现dynein、Lis1以及其他一些胞质蛋白参与调控微管和细胞核的连接,但还没有找到参与这种连接的核膜蛋白。在本论文第三章所述,我和张晓昌博十合作发现SUN蛋白SUN1、SUN2和KASH蛋白Syne-1/Nesprin-1、Syne-2/Nesprin-2通过微管动力蛋白dynein/dynactin、kinesin和微管连接,介导中心体-细胞核偶联,对小鼠大脑神经细胞发生和迁移起至关重要的作用。
和大脑中神经细胞迁移类似,在哺乳动物视网膜发育中,细胞核的迁移和定位对于视锥和视杆光感受细胞的发育和定位也是至关重要的。在光感受细胞前体细胞分裂周期中,前体细胞的细胞核在视网膜生发层的顶端和基端往返运动,这一过程被称为细胞间期细胞核迁移(interkinetic nuclear migration, INM),新形成的光感受细胞通过细胞核迁移形成外核层。如本论文第四章所述,我和俞珏华博士研究了KASH蛋白Syne-2/Nesprin-2和SUN蛋白SUN1、SUN2在1NM和光感受细胞核迁移中的作用。Syne-2/Nesprin-2单敲除或者Sun1Sun2双敲除造成外核层明显变薄、光感受细胞核定位异常,从而导致视网膜电生理缺陷,这种细胞核迁移是由SUN1蛋白和SUN2蛋白定位Syne-2/Nesprin-2蛋白到核膜上形成复合体,通过微管动力蛋白dynein/dynactin和kinesin连接微管和细胞核,从而调控细胞核在视网膜中的迁移。
DNA损伤修复是生物体正常生长发育所必需的,DNA损伤修复缺陷将破坏基因组稳定性,导致免疫缺陷、肿瘤以及衰老等疾病。如本论文第五章所述,我正在研究SUN1和SUN2在DNA损伤修复中的功能。初步实验数据表明,Sun1Sun2双敲除小鼠胚胎成纤维细胞增殖能力下降,DNA损伤反应信号水平降低,对于DNA损伤的反应滞后。同时我还发现SUN1和SUN2与内质网钙调蛋白Reticulocalbin-2(Rcn2)存在相互作用,这提示SUN1和SUN2可能通过Rcn2激活ERK/MAPK信号通路,进而激活DNA损伤反应信号,修复DNA损伤。我正在进一步开展实验研究这一分子机制的具体过程,这可能对认识核纤层蛋白病(Laminopathies)这一大类由核膜蛋白突变引起的早衰或肿瘤易发病的分子机制提供新的线索。
Nuclear migration and positioning are essential for many biological processes. Prior to our studies, several studies have shown the functions of microtubule and actin cytoskeletal system in nuclear migration and positioning. However, the roles of nuclear envelope proteins in these processes were largely unknown. SUN proteins and KASH proteins are two families of nuclear envelope proteins, which locate through the inner nuclear membrane and outer nuclear membrane, respectively. Although studies in yeast, worms, flies, zebrafish and cultured mammalian cells have revealed their roles in nuclear migration and positioning, their roles in mammalian development remained to be further studied. During the research for my Ph.D. thesis, I carried out genetic analysis in mouse and uncovered that SUN1, SUN2, Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in myonuclear anchorage, neurogenesis, neuronal migration, and DNA damage response.
How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei, named non-synaptic nuclei, are evenly distributed at the periphery of each cell, with 3-8 nuclei, named synaptic nuclei, anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain-containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain-containing proteins (SUN proteins) had been shown to interact with KASH domain-containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice were unknown. As described in Chapter 2, I collaborated with Xiaochang and found that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or ail 4 Sun 1/2 wild-type alleles revealed a gene dosage effect on synapiic nuciear anchorage. The organization of nonsynaptic nuclei was also shown to be disrupted in Sun 1/2 doubleknockout (DKO) mice. We further showed that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.
Nuclear movement is critical during neurogenesis and neuronal migration, which are fundamental for mammalian brain development. Although dynein, Lisl, and other cytoplasmic proteins are known for their roles in connecting microtubules to the nucleus during interkinetic nuclear migration (INM) and nucleokinesis, the factors connecting dynein/Lis1 to the nuclear envelope (NE) remain to be determined. As described in Chapter 3, I collaborated with Xiaochang Zhang to find that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. We also showed that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. Syne-2 is connected to the centrosome through interactions with both dynein/dynactin and kinesin complexes.
Nuclear movement relative to cell bodies is a fundamental process during certain aspects of mammalian retinal development. During the generation of photoreceptor cells in the cell division cycle, the nuclei of progenitors oscillate between the apical and basal surface of the neuroblastic layer (NBL). This process is termed as interkinetic nuclear migration (INM). Furthermore, newly formed photoreceptor cells migrate and form the outer nuclear layer (ONL). As described in Chapter 4, I collaborated with Juehua Yu to demonstrate that a KASH domain-containing protein, Syne-2/Nesprin-2, as well as SUN domain-containing proteins, SUN1 and SUN2, play critical roles during INM and photoreceptor cell migration in the mouse retina. A deletion mutation of Syne-2/Nesprin-2 or double mutations of Sun1 and Sun2 caused severe reduction of the thickness of ONL, mislocalization of photoreceptor nuclei, and profound electrophysiological dysfunction of the retina characterized with the reduction of a-and b-wave amplitudes. We also provided evidence that Syne-2/Nesprin-2 forms complexes with either SUN1 or SUN2 at the nuclear envelope to connect the nucleus with dynein/dynactin and kinesin molecular motors during the nuclear migrations in the retina. These key retinal developmental signaling results have advanced our understanding of the mechanism of nuclear migration in mammalian retina.
DNA damage response and repair is critical for normal development and disease pathyology. Defects in DNA damage response and repair processes may cause gene mutation and genomic instability which could lead to immunodeficiency, cancer and premature aging. Chapter 5 describes my analysis of the functions of SUN1 and SUN2 in DNA damage response (DDR). I found that the Sun1 Sun2 double knockout MEFs grows slowly, and that the DDR signals were decreased in Sun1-/-Sun2-/- MEFs. In addition, I found that SUN1 and SUN2 interact with a Calcium-binding protein, Reticulocalbin-2 (Rcn2) for this function. I propose that through binding with Rcn2, SUN1 and SUN2 activate the ERK/MAPK pathway, which then phosphorylates the DDR proteins such as ATM andγ-H2AX. I am carrying out experiments to test this hypothesis. This study will help us understand the molecular mechanism involved in a group of human diseases called Laminopathy, which are caused by the mutations in nuclear envelope proteins.
哺乳动物的骨骼肌细胞是由上百个肌原细胞融合而成的合胞体,每个细胞中有上百个细胞核按一定间距分布在细胞膜下表面,这些细胞核被称为非突触下细胞核,另有3-8个细胞核锚定在骨骼肌神经肌肉接头下,被称为突触下细胞核。我们提出的问题是SUN蛋白和KASH蛋白是否决定这些细胞核在细胞中的精确定位。我们以前的研究发现KASH蛋白Syne-1/Nesprin-1对于小鼠骨骼肌突触下细胞核和非突触下细胞核的锚定都必不可少,但还不知道SUN蛋白是否也参与这些过程。如本论文第二章所述,我和张晓昌博士合作发现仅缺失Sun1基因导致突触下细胞核的锚定被部分破坏,缺失Sun1和Sun2基因的3个甚至4个等位基因后,突触下细胞核的锚定缺陷更加严重,这说明SUN1和SUN2对于突触下细胞核的锚定有剂量效应。我进一步发现在Sun1Sun2双敲除骨骼肌细胞中,非突触下细胞核的锚定被破坏,Syne-1也不能定位在核膜上。这些结果说明在骨骼肌细胞核的锚定中,SUN1和SUN2通过定位Syne-1到核膜上,从而连接细胞核与细胞骨架,调节细胞核在骨骼肌细胞中的定位。
哺乳动物大脑发育伴随有大量的神经细胞发生和迁移,细胞核的移动对于这两个过程都至关重要。研究发现dynein、Lis1以及其他一些胞质蛋白参与调控微管和细胞核的连接,但还没有找到参与这种连接的核膜蛋白。在本论文第三章所述,我和张晓昌博十合作发现SUN蛋白SUN1、SUN2和KASH蛋白Syne-1/Nesprin-1、Syne-2/Nesprin-2通过微管动力蛋白dynein/dynactin、kinesin和微管连接,介导中心体-细胞核偶联,对小鼠大脑神经细胞发生和迁移起至关重要的作用。
和大脑中神经细胞迁移类似,在哺乳动物视网膜发育中,细胞核的迁移和定位对于视锥和视杆光感受细胞的发育和定位也是至关重要的。在光感受细胞前体细胞分裂周期中,前体细胞的细胞核在视网膜生发层的顶端和基端往返运动,这一过程被称为细胞间期细胞核迁移(interkinetic nuclear migration, INM),新形成的光感受细胞通过细胞核迁移形成外核层。如本论文第四章所述,我和俞珏华博士研究了KASH蛋白Syne-2/Nesprin-2和SUN蛋白SUN1、SUN2在1NM和光感受细胞核迁移中的作用。Syne-2/Nesprin-2单敲除或者Sun1Sun2双敲除造成外核层明显变薄、光感受细胞核定位异常,从而导致视网膜电生理缺陷,这种细胞核迁移是由SUN1蛋白和SUN2蛋白定位Syne-2/Nesprin-2蛋白到核膜上形成复合体,通过微管动力蛋白dynein/dynactin和kinesin连接微管和细胞核,从而调控细胞核在视网膜中的迁移。
DNA损伤修复是生物体正常生长发育所必需的,DNA损伤修复缺陷将破坏基因组稳定性,导致免疫缺陷、肿瘤以及衰老等疾病。如本论文第五章所述,我正在研究SUN1和SUN2在DNA损伤修复中的功能。初步实验数据表明,Sun1Sun2双敲除小鼠胚胎成纤维细胞增殖能力下降,DNA损伤反应信号水平降低,对于DNA损伤的反应滞后。同时我还发现SUN1和SUN2与内质网钙调蛋白Reticulocalbin-2(Rcn2)存在相互作用,这提示SUN1和SUN2可能通过Rcn2激活ERK/MAPK信号通路,进而激活DNA损伤反应信号,修复DNA损伤。我正在进一步开展实验研究这一分子机制的具体过程,这可能对认识核纤层蛋白病(Laminopathies)这一大类由核膜蛋白突变引起的早衰或肿瘤易发病的分子机制提供新的线索。
Nuclear migration and positioning are essential for many biological processes. Prior to our studies, several studies have shown the functions of microtubule and actin cytoskeletal system in nuclear migration and positioning. However, the roles of nuclear envelope proteins in these processes were largely unknown. SUN proteins and KASH proteins are two families of nuclear envelope proteins, which locate through the inner nuclear membrane and outer nuclear membrane, respectively. Although studies in yeast, worms, flies, zebrafish and cultured mammalian cells have revealed their roles in nuclear migration and positioning, their roles in mammalian development remained to be further studied. During the research for my Ph.D. thesis, I carried out genetic analysis in mouse and uncovered that SUN1, SUN2, Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in myonuclear anchorage, neurogenesis, neuronal migration, and DNA damage response.
How the nuclei in mammalian skeletal muscle fibers properly position themselves relative to the cell body is an interesting and important cell biology question. In the syncytial skeletal muscle cells, more than 100 nuclei, named non-synaptic nuclei, are evenly distributed at the periphery of each cell, with 3-8 nuclei, named synaptic nuclei, anchored beneath the neuromuscular junction (NMJ). Our previous studies revealed that the KASH domain-containing Syne-1/Nesprin-1 protein plays an essential role in anchoring both synaptic and nonsynaptic myonuclei in mice. SUN domain-containing proteins (SUN proteins) had been shown to interact with KASH domain-containing proteins (KASH proteins) at the nuclear envelope (NE), but their roles in nuclear positioning in mice were unknown. As described in Chapter 2, I collaborated with Xiaochang and found that the synaptic nuclear anchorage is partially perturbed in Sun1, but not in Sun2, knockout mice. Disruption of 3 or ail 4 Sun 1/2 wild-type alleles revealed a gene dosage effect on synapiic nuciear anchorage. The organization of nonsynaptic nuclei was also shown to be disrupted in Sun 1/2 doubleknockout (DKO) mice. We further showed that the localization of Syne-1 to the NE of muscle cells is disrupted in Sun1/2 DKO mice. These results clearly indicate that SUN1 and SUN2 function critically in skeletal muscle cells for Syne-1 localization at the NE, which is essential for proper myonuclear positioning.
Nuclear movement is critical during neurogenesis and neuronal migration, which are fundamental for mammalian brain development. Although dynein, Lisl, and other cytoplasmic proteins are known for their roles in connecting microtubules to the nucleus during interkinetic nuclear migration (INM) and nucleokinesis, the factors connecting dynein/Lis1 to the nuclear envelope (NE) remain to be determined. As described in Chapter 3, I collaborated with Xiaochang Zhang to find that the SUN-domain proteins SUN1 and SUN2 and the KASH-domain proteins Syne-1/Nesprin-1 and Syne-2/Nesprin-2 play critical roles in neurogenesis and neuronal migration in mice. We also showed that SUN1 and SUN2 redundantly form complexes with Syne-2 to mediate the centrosome-nucleus coupling during both INM and radial neuronal migration in the cerebral cortex. Syne-2 is connected to the centrosome through interactions with both dynein/dynactin and kinesin complexes.
Nuclear movement relative to cell bodies is a fundamental process during certain aspects of mammalian retinal development. During the generation of photoreceptor cells in the cell division cycle, the nuclei of progenitors oscillate between the apical and basal surface of the neuroblastic layer (NBL). This process is termed as interkinetic nuclear migration (INM). Furthermore, newly formed photoreceptor cells migrate and form the outer nuclear layer (ONL). As described in Chapter 4, I collaborated with Juehua Yu to demonstrate that a KASH domain-containing protein, Syne-2/Nesprin-2, as well as SUN domain-containing proteins, SUN1 and SUN2, play critical roles during INM and photoreceptor cell migration in the mouse retina. A deletion mutation of Syne-2/Nesprin-2 or double mutations of Sun1 and Sun2 caused severe reduction of the thickness of ONL, mislocalization of photoreceptor nuclei, and profound electrophysiological dysfunction of the retina characterized with the reduction of a-and b-wave amplitudes. We also provided evidence that Syne-2/Nesprin-2 forms complexes with either SUN1 or SUN2 at the nuclear envelope to connect the nucleus with dynein/dynactin and kinesin molecular motors during the nuclear migrations in the retina. These key retinal developmental signaling results have advanced our understanding of the mechanism of nuclear migration in mammalian retina.
DNA damage response and repair is critical for normal development and disease pathyology. Defects in DNA damage response and repair processes may cause gene mutation and genomic instability which could lead to immunodeficiency, cancer and premature aging. Chapter 5 describes my analysis of the functions of SUN1 and SUN2 in DNA damage response (DDR). I found that the Sun1 Sun2 double knockout MEFs grows slowly, and that the DDR signals were decreased in Sun1-/-Sun2-/- MEFs. In addition, I found that SUN1 and SUN2 interact with a Calcium-binding protein, Reticulocalbin-2 (Rcn2) for this function. I propose that through binding with Rcn2, SUN1 and SUN2 activate the ERK/MAPK pathway, which then phosphorylates the DDR proteins such as ATM andγ-H2AX. I am carrying out experiments to test this hypothesis. This study will help us understand the molecular mechanism involved in a group of human diseases called Laminopathy, which are caused by the mutations in nuclear envelope proteins.
引文
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