内蒙古白绒山羊转VEGF基因细胞系的建立与VEGF基因新剪接变体（VEGF138）的发现
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摘要
目的：克隆内蒙古白绒山羊VEGF基因,构建毛囊特异性表达载体PCDsRed2-KV,稳定转染绒山羊胎儿成纤维细胞,筛选获得稳定表达红色荧光蛋白和毛囊特异表达VEGF的转基因的细胞克隆。检测VEGF基因在皮肤细胞中的表达。此外本研究尝试发现新的剪接变体。检测VEGF 138是否存在于内蒙古白绒山羊胎儿成纤维细胞中,检测内蒙古白绒山羊脑、心脏、肝、脾、肾、肺6种组织中VEGF 164、VEGF138和VEGF 120三种剪接变体的mRNA丰度。
方法：采用RT-PCR技术克隆内蒙古白绒山羊VEGF基因cDNA,并进行生物信息学分析。以pCDsRed2载体为基本骨架将VEGF 164基因cDNA序列亚克隆到KAP6-1启动子下游,接续连接红色荧光蛋白表达元件DsRed,构建VEGF 164基因毛囊特异表达载体pCDsRed2-KV。外源表达载体以lipofectamineTM2000介导转染胎儿成纤维细胞,G418筛选获得稳定转染的细胞克隆,PCR鉴定外源基因在细胞基因组中的整合。pCDsRed2-KV载体转染内蒙古白绒山羊皮肤成纤维细胞,RT-PCR检测VEGF mRNA表达量,Western blot检测VEGF蛋白的表达。利用Taqman探针荧光实时定量方法确认新发现的剪接变体VEGF138存在于内蒙古白绒山羊胎儿成纤维细胞中。采用SYBR Green荧光实时定量检测VEGF164、VEGF138和VEGF 120三种剪接变体在内蒙古白绒山羊6中组织中的mRNA丰度。
结果：克隆到内蒙古白绒山羊VEDF基因的三个剪接变体VEGF164、VEGF138和VEGF120的cDNA序列,其中VEGF138是首次发现。VEGF164 cDNA序列573bp,包含了全长ORF,编码190个氨基酸,N端的26个碱基为信号肽序列；VEGF138 cDNA序列495bp,包含了全长ORF,编码164个氨基酸,N端的26个碱基为信号肽序列；VEGF120 cDNA序列441bp,包含了全长ORF,编码146个氨基酸,N端的26个碱基为信号肽序列。VEGF164、VEGF138和VEGF120三种剪接变体在内蒙古白绒山羊脑、心脏、肝、脾、肾、肺组织中均有表达,但VEGF138的mRNA丰度远小于VEGF165和VEGF120。测序结果显示表达载体pCDsRed2-KV中,VEGF164基因正确连接在毛囊特异性启动子KAP6-1下游,顺序连接CMV启动子和红色荧光蛋白基因,载体构建正确。筛选得到转基因细胞克隆,PCR检测显示外源KAP6-1启动子和VEGF164基因整合到细胞基因组中。转染VEGF基因的内蒙古白绒山羊皮肤细胞中,VEGF mRNA表达量和蛋白表达量均有明显增加。
结论：成功构建稳定表达红色荧光蛋白和毛囊特异表达VEGF164的真核表达载体,稳定转染绒山羊胎儿成纤维细胞,并为进一步通过转基因克隆技术获得毛囊特异性超表达VEGF164基因绒山羊新品系提供了条件。VEGF基因在内蒙古白绒山皮肤细胞中表达为转基因绒山羊新品系建立提供了理论基础。VEGF基因在内蒙古白绒山羊至少有3个剪接变体,分别是VEGF164、VEGF138和VEGF120,其中VEGF138是首次发现。三种剪接变体在内蒙古白绒山羊脑、心脏、肝、脾、肾、肺组织中均有表达,VEGF138的mRNA丰度远小于VEGF165和VEGF120,为进一步研究VEGF不同剪接变体的功能奠定了基础。
Objective:To clone the cDNA of VEGF gene in Inner Mongolia Cashmere Goat, Constructing a eukaryotic expression vector pCDsRed2-KV of cashmere goat VEGF164 (vascular endothelial cell growth factor) gene. To transfer pCDsRed2-KV into Inner Mongolia Cashmere goat (Capra hircus) fetal fibroblast (GFb) cells to obtain a transgenic cell clones, which stable expresses red fluorescence and expresses VEGF gene in hair follicle cells specifically. To examin VEGF expression in Inner Mongolia Cashmere goat (Capra hircus) skin cells which tansfected pCDsRed2-KV. In addition, to discovering potential splice variants of transcription products of VEGF gene. To verify the existence of VEGF 138 splice variant in Inner Mongolia Cashmere Goat fetal fibroblast cells. To examine relative abundance of three splice variants of VEGF mRNA in brain, heart, liver, spleen, kidney and lung of Inner Mongolia Cashmere Goats.
Method:VEGF gene cDNA was cloned by RT-PCR. The nucleotide sequence was analyzed by bioinformatics. pCDsRed2-KV, a hair-follicle-specific expression vector of VEGF164, was constructed by connecting VEGF164 gene to downstream of KAP6-1 promoter, and then inserting the KAP6-1 promoter-VEGF 164 gene fragment into the basic vector pCDsRed2, which contains a DsRed expression unit. The Inner Mongolia Cashmere goat fetal fibroblast (GFb) cells were transfected with the expression vector by lipofectamineTM2000. Transgenic cell clones were obtained after screening by G418. The recombinant of exogenous DNA was identified by polymerase chain reaction. In order to make sure pCDsRed2-KV is hair-follicle-specific expression vector, we transfected the expression vector into Inner Mongolia Cashmere goat skin cells and detected expression. Expression of VEGF examined by RT-PCR and Western blot assy. Quantitative real-time PCR (Taqman) analysis VEGF 138 mRNA, distribute in Inner Mongolia Cashmere goat (Capra hircus) fetal fibroblast (GFb) cells. The relative abundance of three splice variants of VEGF mRNA, measured in six tissues, by Quantitative real-time PCR.
Result:We got CDS fragments of VEGF 164, VEGF 120 and new isoform VEGF138. VEGF138 was discovered for the first time. The VEGF164 gene was 573 bp in length, including an intact ORF which formed by 190 amino acids.26 amino acids of N'end are signal peptidein. The VEGF 138 gene was 495 bp in length, including an intact ORF which formed by 164 amino acids.26 amino acids of N'end are signal peptidein. The VEGF 120 gene was 441 bp in length, including an intact ORF which formed by 146 amino acids.26 amino acids of N' end are signal peptidein. VEGF 164, VEGF 138 and VEGF 138 express in brain, heart, liver, spleen, kidney and lung. VEGF 138 mRNA is less than VEGF 164 and VEGF 120. The sequencing result showed the VEGF 164 gene was connected properly to the downstream of pKAP6-1, then the CMV promoter and the DsRed2 gene in sequence. Exogenous DNA in the cell clones was examined by PCR and the promoter KAP6-1 as well as VEGF164 gene has been integrated into GFb cells genome stably. VEGF mRNA and protein increase significantly in transfected Inner Mongolia Cashmere goat (Capra hircus) skin cells.
Conclusion:A hair-follicle-cell-specific expression vector of VEGF 164 gene was constructed successfully and transfered into GFb cells. These data provide a way to obtain the transgenic goat by nuclear transfer in the future. VEGF expression increase apparently in transfected Inner Mongolia Cashmere goat (Capra hircus) skin cells that provide a theory to obtain the transgenic goat. There are three forms of VEGF at least in Inner Mongolia Cashmere goat (Capra hircus). They are VEGF 164, VEGF138 and VEGF120; and VEGF138 was discovered for the first time. Three forms of VEGF express in brain, heart, liver, spleen, kidney and lung. VEGF 138 mRNA is less than VEGF 164 and VEGF 120. This information provides a way to study function of three forms of VEGF.
方法：采用RT-PCR技术克隆内蒙古白绒山羊VEGF基因cDNA,并进行生物信息学分析。以pCDsRed2载体为基本骨架将VEGF 164基因cDNA序列亚克隆到KAP6-1启动子下游,接续连接红色荧光蛋白表达元件DsRed,构建VEGF 164基因毛囊特异表达载体pCDsRed2-KV。外源表达载体以lipofectamineTM2000介导转染胎儿成纤维细胞,G418筛选获得稳定转染的细胞克隆,PCR鉴定外源基因在细胞基因组中的整合。pCDsRed2-KV载体转染内蒙古白绒山羊皮肤成纤维细胞,RT-PCR检测VEGF mRNA表达量,Western blot检测VEGF蛋白的表达。利用Taqman探针荧光实时定量方法确认新发现的剪接变体VEGF138存在于内蒙古白绒山羊胎儿成纤维细胞中。采用SYBR Green荧光实时定量检测VEGF164、VEGF138和VEGF 120三种剪接变体在内蒙古白绒山羊6中组织中的mRNA丰度。
结果：克隆到内蒙古白绒山羊VEDF基因的三个剪接变体VEGF164、VEGF138和VEGF120的cDNA序列,其中VEGF138是首次发现。VEGF164 cDNA序列573bp,包含了全长ORF,编码190个氨基酸,N端的26个碱基为信号肽序列；VEGF138 cDNA序列495bp,包含了全长ORF,编码164个氨基酸,N端的26个碱基为信号肽序列；VEGF120 cDNA序列441bp,包含了全长ORF,编码146个氨基酸,N端的26个碱基为信号肽序列。VEGF164、VEGF138和VEGF120三种剪接变体在内蒙古白绒山羊脑、心脏、肝、脾、肾、肺组织中均有表达,但VEGF138的mRNA丰度远小于VEGF165和VEGF120。测序结果显示表达载体pCDsRed2-KV中,VEGF164基因正确连接在毛囊特异性启动子KAP6-1下游,顺序连接CMV启动子和红色荧光蛋白基因,载体构建正确。筛选得到转基因细胞克隆,PCR检测显示外源KAP6-1启动子和VEGF164基因整合到细胞基因组中。转染VEGF基因的内蒙古白绒山羊皮肤细胞中,VEGF mRNA表达量和蛋白表达量均有明显增加。
结论：成功构建稳定表达红色荧光蛋白和毛囊特异表达VEGF164的真核表达载体,稳定转染绒山羊胎儿成纤维细胞,并为进一步通过转基因克隆技术获得毛囊特异性超表达VEGF164基因绒山羊新品系提供了条件。VEGF基因在内蒙古白绒山皮肤细胞中表达为转基因绒山羊新品系建立提供了理论基础。VEGF基因在内蒙古白绒山羊至少有3个剪接变体,分别是VEGF164、VEGF138和VEGF120,其中VEGF138是首次发现。三种剪接变体在内蒙古白绒山羊脑、心脏、肝、脾、肾、肺组织中均有表达,VEGF138的mRNA丰度远小于VEGF165和VEGF120,为进一步研究VEGF不同剪接变体的功能奠定了基础。
Objective:To clone the cDNA of VEGF gene in Inner Mongolia Cashmere Goat, Constructing a eukaryotic expression vector pCDsRed2-KV of cashmere goat VEGF164 (vascular endothelial cell growth factor) gene. To transfer pCDsRed2-KV into Inner Mongolia Cashmere goat (Capra hircus) fetal fibroblast (GFb) cells to obtain a transgenic cell clones, which stable expresses red fluorescence and expresses VEGF gene in hair follicle cells specifically. To examin VEGF expression in Inner Mongolia Cashmere goat (Capra hircus) skin cells which tansfected pCDsRed2-KV. In addition, to discovering potential splice variants of transcription products of VEGF gene. To verify the existence of VEGF 138 splice variant in Inner Mongolia Cashmere Goat fetal fibroblast cells. To examine relative abundance of three splice variants of VEGF mRNA in brain, heart, liver, spleen, kidney and lung of Inner Mongolia Cashmere Goats.
Method:VEGF gene cDNA was cloned by RT-PCR. The nucleotide sequence was analyzed by bioinformatics. pCDsRed2-KV, a hair-follicle-specific expression vector of VEGF164, was constructed by connecting VEGF164 gene to downstream of KAP6-1 promoter, and then inserting the KAP6-1 promoter-VEGF 164 gene fragment into the basic vector pCDsRed2, which contains a DsRed expression unit. The Inner Mongolia Cashmere goat fetal fibroblast (GFb) cells were transfected with the expression vector by lipofectamineTM2000. Transgenic cell clones were obtained after screening by G418. The recombinant of exogenous DNA was identified by polymerase chain reaction. In order to make sure pCDsRed2-KV is hair-follicle-specific expression vector, we transfected the expression vector into Inner Mongolia Cashmere goat skin cells and detected expression. Expression of VEGF examined by RT-PCR and Western blot assy. Quantitative real-time PCR (Taqman) analysis VEGF 138 mRNA, distribute in Inner Mongolia Cashmere goat (Capra hircus) fetal fibroblast (GFb) cells. The relative abundance of three splice variants of VEGF mRNA, measured in six tissues, by Quantitative real-time PCR.
Result:We got CDS fragments of VEGF 164, VEGF 120 and new isoform VEGF138. VEGF138 was discovered for the first time. The VEGF164 gene was 573 bp in length, including an intact ORF which formed by 190 amino acids.26 amino acids of N'end are signal peptidein. The VEGF 138 gene was 495 bp in length, including an intact ORF which formed by 164 amino acids.26 amino acids of N'end are signal peptidein. The VEGF 120 gene was 441 bp in length, including an intact ORF which formed by 146 amino acids.26 amino acids of N' end are signal peptidein. VEGF 164, VEGF 138 and VEGF 138 express in brain, heart, liver, spleen, kidney and lung. VEGF 138 mRNA is less than VEGF 164 and VEGF 120. The sequencing result showed the VEGF 164 gene was connected properly to the downstream of pKAP6-1, then the CMV promoter and the DsRed2 gene in sequence. Exogenous DNA in the cell clones was examined by PCR and the promoter KAP6-1 as well as VEGF164 gene has been integrated into GFb cells genome stably. VEGF mRNA and protein increase significantly in transfected Inner Mongolia Cashmere goat (Capra hircus) skin cells.
Conclusion:A hair-follicle-cell-specific expression vector of VEGF 164 gene was constructed successfully and transfered into GFb cells. These data provide a way to obtain the transgenic goat by nuclear transfer in the future. VEGF expression increase apparently in transfected Inner Mongolia Cashmere goat (Capra hircus) skin cells that provide a theory to obtain the transgenic goat. There are three forms of VEGF at least in Inner Mongolia Cashmere goat (Capra hircus). They are VEGF 164, VEGF138 and VEGF120; and VEGF138 was discovered for the first time. Three forms of VEGF express in brain, heart, liver, spleen, kidney and lung. VEGF 138 mRNA is less than VEGF 164 and VEGF 120. This information provides a way to study function of three forms of VEGF.
引文
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