CSX/Nkx2.5基因和CCNL2基因在大鼠胚胎心脏发育过程中时空表达的研究
摘要
【目的】检测CSX/Nkx2.5基因在大鼠胚胎心脏发育过程中的mRNA表达变化及其蛋白定位。
【方法】取大鼠胚胎d12、d15、d17、d19心脏,采用半定量反转录聚合酶链反应(RT-PCR)技术检测心脏组织中CSX/Nkx2.5基因mRNA的表达丰度,并应用免疫组化的方法对其进行蛋白定位分析。
【结果】在大鼠胚胎d12、d15、d17、d19心脏中,CSX/Nkx2.5基因mRNA均有表达,且呈逐渐上调趋势;其蛋白主要表达于心房、心室壁和肌小梁等处心肌组织,而在心内膜、心外膜、瓣膜、流出道、大血管等处未见表达。
【结论】CSX/Nkx2.5基因的表达随大鼠胚胎心脏的生长发育逐渐上调,且特异表达于胚胎心脏心肌细胞的细胞核,与心脏发育密切相关。
【目的】检测大鼠胚胎心脏发育过程中CCNL2(cyclin L2)基因mRNA的定位表达变化。
【方法】取大鼠胚胎d11-d15心脏,应用原位杂交技术,检测胚胎心脏发育不同时期CCNL2基因mRNA的定位情况。
【结果】在大鼠胚胎d11-d15心脏中,CCNL2基因主要表达于心内膜垫、瓣膜、流出道、大动脉等处,心房、心室、肌小梁等心肌组织中亦可见表达。
【结论】CCNL2基因表达于心内膜垫、瓣膜、流出道、大动脉根部,房室肌等胚胎心脏组织的细胞核中,可能参与心脏发育。
[Objective] To investigate the change of CSX/Nkx2.5 gene mRNA expression and its protein location in the developing rat hearts.
[Methods] Embryonic hearts of normal rats were obtained on the 12th, 15th, 17th and 19th day during embryonic period. Reverse transcription polymerase chain reaction (RT-PCR) was used to reveal CSX/Nkx2.5 gene mRNA expression, and Immunohistochemistry for its protein location. The results were analyzed by the statistical method of One-way ANOVA.
[Results] With the development of rat hearts, the expression levels of CSX/Nkx2.5 gene mRNA were up-regulated ,CSX/Nkx2.5 protein was mainly expressed in the atria , ventricles and trabecular muscles , while it was not detected in the endocardium, the epicardium , the valvular tissues , outflow tracks and large arteries.
[Conclusions] CSX/Nkx2.5 gene is up-regulated in the rat heart and specifically express in the nucleus of cardiac muscle cell. It suggests that CSX/Nkx2.5 should play an important role in the fetal heart development.
[Objective] To investigate CCNL2 ( cyclin L2 ) gene mRNA location during the development of Rattus heart.
[Methods] Embryonic hearts of normal rats were obtained from the 11th day to the 15th day during embryonic period. CCNL2 gene mRNA location was detected by in situ hybridization.
[Results] CCNL2 gene mRNA was mainly expressed in endocardial cushion , valves , outflow tracks and large arteries, and also expressed in atria, ventricles and trabecular muscles.
[Conclusion] CCNL2 gene is expressed in the cell nucleus of endocardial cushion , valves , outflow tracks , large arteries and atrial ventricular myocardium. CCNL2 gene may play a role in the heart development.
【方法】取大鼠胚胎d12、d15、d17、d19心脏,采用半定量反转录聚合酶链反应(RT-PCR)技术检测心脏组织中CSX/Nkx2.5基因mRNA的表达丰度,并应用免疫组化的方法对其进行蛋白定位分析。
【结果】在大鼠胚胎d12、d15、d17、d19心脏中,CSX/Nkx2.5基因mRNA均有表达,且呈逐渐上调趋势;其蛋白主要表达于心房、心室壁和肌小梁等处心肌组织,而在心内膜、心外膜、瓣膜、流出道、大血管等处未见表达。
【结论】CSX/Nkx2.5基因的表达随大鼠胚胎心脏的生长发育逐渐上调,且特异表达于胚胎心脏心肌细胞的细胞核,与心脏发育密切相关。
【目的】检测大鼠胚胎心脏发育过程中CCNL2(cyclin L2)基因mRNA的定位表达变化。
【方法】取大鼠胚胎d11-d15心脏,应用原位杂交技术,检测胚胎心脏发育不同时期CCNL2基因mRNA的定位情况。
【结果】在大鼠胚胎d11-d15心脏中,CCNL2基因主要表达于心内膜垫、瓣膜、流出道、大动脉等处,心房、心室、肌小梁等心肌组织中亦可见表达。
【结论】CCNL2基因表达于心内膜垫、瓣膜、流出道、大动脉根部,房室肌等胚胎心脏组织的细胞核中,可能参与心脏发育。
[Objective] To investigate the change of CSX/Nkx2.5 gene mRNA expression and its protein location in the developing rat hearts.
[Methods] Embryonic hearts of normal rats were obtained on the 12th, 15th, 17th and 19th day during embryonic period. Reverse transcription polymerase chain reaction (RT-PCR) was used to reveal CSX/Nkx2.5 gene mRNA expression, and Immunohistochemistry for its protein location. The results were analyzed by the statistical method of One-way ANOVA.
[Results] With the development of rat hearts, the expression levels of CSX/Nkx2.5 gene mRNA were up-regulated ,CSX/Nkx2.5 protein was mainly expressed in the atria , ventricles and trabecular muscles , while it was not detected in the endocardium, the epicardium , the valvular tissues , outflow tracks and large arteries.
[Conclusions] CSX/Nkx2.5 gene is up-regulated in the rat heart and specifically express in the nucleus of cardiac muscle cell. It suggests that CSX/Nkx2.5 should play an important role in the fetal heart development.
[Objective] To investigate CCNL2 ( cyclin L2 ) gene mRNA location during the development of Rattus heart.
[Methods] Embryonic hearts of normal rats were obtained from the 11th day to the 15th day during embryonic period. CCNL2 gene mRNA location was detected by in situ hybridization.
[Results] CCNL2 gene mRNA was mainly expressed in endocardial cushion , valves , outflow tracks and large arteries, and also expressed in atria, ventricles and trabecular muscles.
[Conclusion] CCNL2 gene is expressed in the cell nucleus of endocardial cushion , valves , outflow tracks , large arteries and atrial ventricular myocardium. CCNL2 gene may play a role in the heart development.
引文
[1] Olson EN. Gene regulatory networks in the evolution and development of the heart [J]. Science 2006, 313(5795):1922-1927.
[2] Sakabe M, Matsui H, Sakata H, et al. Understanding heart development and congenital heart defects through developmental biology: a segmental approach. Congenit Anom (Kyoto) [ J]. 2005, 45(4):107-118.
[3] Clark KL, Yutzey KE, Benson DW. Transcription factors and congenital heart defects[ J]. Annu RevPhysiol 2006, 68 (1) :97-121.
[4] Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, raill TA, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). The New England journal of medicine1994;330:885-891.
[5] Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, et al. Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Human mutation 2003;22:372-377.
[6] Casey B, Devoto M, Jones KL, Ballabio A. Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nature genetics 1993;5:403-407.
[7] Gruber PJ. Cardiac development: new concepts [J] . Clin Perinatol, 2005,32 (4) :845-855.
[8] Arai Y, Funatsu N, Numayama-Tsuruta K, et al. Role of Fabp7, a downstream gene of Pax6, in the maintenance of neuroepithelial cells during early embryonic development of the rat cortex[ J]. Neurosci, 2005,25:9752-61.
[9] Gonzalez-Reyes S, Fernandez-Dumont V, Calonge WM, et al. Expression of Connexin 43 in the hearts of rat embryos exposed to nitrofen and effects of vitamin A on it[ J]. Pediatr Surg Int, 2006, 22: 61-65.
[10] Stauffer NR, Murphy K. Prenatal diagnosis of congenital heart disease: the beginning[ J]. Crit Care NursQ, 2002; 25 ( 3 ) : 1-7.
[11] Jonathan A, Michael S. Recent advances in cardiac development with therapeutic implications for adult cardiovascular disease [J]. Circulation,2005,112(4):592-597.
[12] Turbay D,Wechsler SB, Blanchard KM, et al. Molecular cloning, chromosomal mapping, and characterization of the human cardiac -specific homeobox gene hCsx[ J]. MolMed, 1996; 2(1) : 86 -96.
[13] Ueyama T , Kasahara H , Ishiwata T, et al. Myocardin expression is regulated by Nkx2. 5 , and its function is required for cardiomyogenesis[ J]. Mol Cell Biol, 2003 ,23 ( 24 ) :9222 - 9232.
[14] Zang MX, Li Y, Xue LX, et al. Cooperative activation of atrial natriuretic peptide promoter by dHAND and MEF2 C[ J]. J Cell Biochem,2004; 93 ( 9 ) : 1255
[15] Bartlett HL, Sutherland L, Kolker SJ, et al . Transient early embryonic expression of Nkx2-5 mutations linked to congenital heart defects in human causes heart defects in Xenopus laevis[ J]. 2007 Sep;236(9):2475-84.
[16]Hao Zhang, Lei Zhou, Rong Yang, et al. Identification of differentially expressed genes in human with ventricular septal defect using suppression subtractive hybridization [J]. Biochem Biophys Res Commun, 2006,342(1): 135-144
[17] Raffin M, Leong LM, Rones MS , et al . Subdivision of the cardiac Nkx2. 5 expression domain into myogenic and nonmyogenic compartments[ J]. Dev Biol, 2000 ,218(2) :326240.
[18] Thompson JT, Rackley MS, O'Brien TX. Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overload[ J]. Am J Physiol. 1998;274 ( 5 Pt 2 ) :H1569-73.
[19] Akazawa H, Komuro I. Roles of cardiac transcription factors in cardiac hypertrophy[ J]. Circ Res. 2003 May 30;92(10):1079-88. Review.
[20] Toko H, Zhu W, Takimoto E, et al. Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart[ J]. J Biol Chem. 2002;277 (27) :24735-24743.
[1]Steven A.Fisher,B.Lowell Langille,et al.Apoptosis During Cardiovascular Development.Circ.Res.2000;87;856-864.
[2]钱玲梅,曹克将,黄元铸,孔祥清,单其俊:房间隔缺损患者心肌组织基因表达谱系特征的初步分析.中华心血管病杂志2003,31(3):180-183.
[3]Zhang H,Zhou L,Yang R,et al.Identification of differentially expressed genes in human heart with ventricular septal defect using suppression subtractive hybridization.Biochem Biophys Res Commun 2006,342(1):135-144.
[4]Wang WD,Huang C J,Lu YF,Hsin JP,Prabhakar VR,Cheng CF,Hwang SP:Heart-targeted overexpression of Nip3a in zebrafish embryos causes abnormal heart development and cardiac dysfunction.Biochem Biophys Res Commun 2006,347(4):979-987.
[5]Wasch R,Cross FR.APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit.Nature 2002;418:556-562.
[6]Duman-Scheel M,Weng L,Xin S,Du W.Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.Nature 2002;417:299-304.
[7]Koepp DM,Schaefer LK,Ye X,et al.Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase.Science 2001; 294:173-177.
[8] Berke JD, Sgambato V, Zhu PP, et al. Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin.Neuron. 2001; 32(2):277-87.
[9] Thackaberry EA, Jiang Z, Johnson CD, et al. Toxicogenomic profile of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the murine fetal heart: modulation of cell cycle and extracellular matrix genes. Toxicol Sci. 2005,88(1):231-234.
[10] Chen HH, Wang YC, Fann MJ. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation . Mol Cell Biol 2006; 26(6):2736-2745.
[11] de Graaf K, Hekerman P, Spelten O, et al.Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors.J Biol Chem. 2004 279(6):4612-4624.
[12] Li HL, Wang TS, Li XY, et al.Overexpression of cyclin L2 induces apoptosis and cell-cycle arrest in human lung cancer cells.Chin Med J (Engl). 2007,120(10):905-909.
[13] Yang L, Li N, Wang C, Yu Y, Yuan L, Zhang M, et al. Cyclin L2, a novel RNA polymerase II-associated cyclin, is involved in pre-mRNA splicing and induces apoptosis of human hepatocellular carcinoma cells. J Biol Chem 2004; 279:11639-11648.
[14] Liu ZJ, Ueda T, Miyazaki T, et al. A critical role for cyclin C in promotion of the hematopoietic cell cycle by cooperation with c-Myc. Mol Cell Biol. 1998;18(6):3445-3454.
[15] Shen H , Kan JL , Green MR. Arginine2serine2rich domains bound at splicing enhancers contact the branchpoint to promote prespliceosome assembly. Mol Cell, 2004 , 13 (3) :3672-3676.
[16] Xiao R, Sun Y, Ding JH, et al . Splicing regulator SC35 is essential for genomic stability and cell proliferation during mammalian organogenesis. Mol Cell Biol. 2007 , 27(15):5393-402.
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[2] Sakabe M, Matsui H, Sakata H, et al. Understanding heart development and congenital heart defects through developmental biology: a segmental approach. Congenit Anom (Kyoto) [ J]. 2005, 45(4):107-118.
[3] Clark KL, Yutzey KE, Benson DW. Transcription factors and congenital heart defects[ J]. Annu RevPhysiol 2006, 68 (1) :97-121.
[4] Basson CT, Cowley GS, Solomon SD, Weissman B, Poznanski AK, raill TA, et al. The clinical and genetic spectrum of the Holt-Oram syndrome (heart-hand syndrome). The New England journal of medicine1994;330:885-891.
[5] Pizzuti A, Sarkozy A, Newton AL, Conti E, Flex E, Digilio MC, et al. Mutations of ZFPM2/FOG2 gene in sporadic cases of tetralogy of Fallot. Human mutation 2003;22:372-377.
[6] Casey B, Devoto M, Jones KL, Ballabio A. Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nature genetics 1993;5:403-407.
[7] Gruber PJ. Cardiac development: new concepts [J] . Clin Perinatol, 2005,32 (4) :845-855.
[8] Arai Y, Funatsu N, Numayama-Tsuruta K, et al. Role of Fabp7, a downstream gene of Pax6, in the maintenance of neuroepithelial cells during early embryonic development of the rat cortex[ J]. Neurosci, 2005,25:9752-61.
[9] Gonzalez-Reyes S, Fernandez-Dumont V, Calonge WM, et al. Expression of Connexin 43 in the hearts of rat embryos exposed to nitrofen and effects of vitamin A on it[ J]. Pediatr Surg Int, 2006, 22: 61-65.
[10] Stauffer NR, Murphy K. Prenatal diagnosis of congenital heart disease: the beginning[ J]. Crit Care NursQ, 2002; 25 ( 3 ) : 1-7.
[11] Jonathan A, Michael S. Recent advances in cardiac development with therapeutic implications for adult cardiovascular disease [J]. Circulation,2005,112(4):592-597.
[12] Turbay D,Wechsler SB, Blanchard KM, et al. Molecular cloning, chromosomal mapping, and characterization of the human cardiac -specific homeobox gene hCsx[ J]. MolMed, 1996; 2(1) : 86 -96.
[13] Ueyama T , Kasahara H , Ishiwata T, et al. Myocardin expression is regulated by Nkx2. 5 , and its function is required for cardiomyogenesis[ J]. Mol Cell Biol, 2003 ,23 ( 24 ) :9222 - 9232.
[14] Zang MX, Li Y, Xue LX, et al. Cooperative activation of atrial natriuretic peptide promoter by dHAND and MEF2 C[ J]. J Cell Biochem,2004; 93 ( 9 ) : 1255
[15] Bartlett HL, Sutherland L, Kolker SJ, et al . Transient early embryonic expression of Nkx2-5 mutations linked to congenital heart defects in human causes heart defects in Xenopus laevis[ J]. 2007 Sep;236(9):2475-84.
[16]Hao Zhang, Lei Zhou, Rong Yang, et al. Identification of differentially expressed genes in human with ventricular septal defect using suppression subtractive hybridization [J]. Biochem Biophys Res Commun, 2006,342(1): 135-144
[17] Raffin M, Leong LM, Rones MS , et al . Subdivision of the cardiac Nkx2. 5 expression domain into myogenic and nonmyogenic compartments[ J]. Dev Biol, 2000 ,218(2) :326240.
[18] Thompson JT, Rackley MS, O'Brien TX. Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overload[ J]. Am J Physiol. 1998;274 ( 5 Pt 2 ) :H1569-73.
[19] Akazawa H, Komuro I. Roles of cardiac transcription factors in cardiac hypertrophy[ J]. Circ Res. 2003 May 30;92(10):1079-88. Review.
[20] Toko H, Zhu W, Takimoto E, et al. Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart[ J]. J Biol Chem. 2002;277 (27) :24735-24743.
[1]Steven A.Fisher,B.Lowell Langille,et al.Apoptosis During Cardiovascular Development.Circ.Res.2000;87;856-864.
[2]钱玲梅,曹克将,黄元铸,孔祥清,单其俊:房间隔缺损患者心肌组织基因表达谱系特征的初步分析.中华心血管病杂志2003,31(3):180-183.
[3]Zhang H,Zhou L,Yang R,et al.Identification of differentially expressed genes in human heart with ventricular septal defect using suppression subtractive hybridization.Biochem Biophys Res Commun 2006,342(1):135-144.
[4]Wang WD,Huang C J,Lu YF,Hsin JP,Prabhakar VR,Cheng CF,Hwang SP:Heart-targeted overexpression of Nip3a in zebrafish embryos causes abnormal heart development and cardiac dysfunction.Biochem Biophys Res Commun 2006,347(4):979-987.
[5]Wasch R,Cross FR.APC-dependent proteolysis of the mitotic cyclin Clb2 is essential for mitotic exit.Nature 2002;418:556-562.
[6]Duman-Scheel M,Weng L,Xin S,Du W.Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E.Nature 2002;417:299-304.
[7]Koepp DM,Schaefer LK,Ye X,et al.Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase.Science 2001; 294:173-177.
[8] Berke JD, Sgambato V, Zhu PP, et al. Dopamine and glutamate induce distinct striatal splice forms of Ania-6, an RNA polymerase II-associated cyclin.Neuron. 2001; 32(2):277-87.
[9] Thackaberry EA, Jiang Z, Johnson CD, et al. Toxicogenomic profile of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the murine fetal heart: modulation of cell cycle and extracellular matrix genes. Toxicol Sci. 2005,88(1):231-234.
[10] Chen HH, Wang YC, Fann MJ. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation . Mol Cell Biol 2006; 26(6):2736-2745.
[11] de Graaf K, Hekerman P, Spelten O, et al.Characterization of cyclin L2, a novel cyclin with an arginine/serine-rich domain: phosphorylation by DYRK1A and colocalization with splicing factors.J Biol Chem. 2004 279(6):4612-4624.
[12] Li HL, Wang TS, Li XY, et al.Overexpression of cyclin L2 induces apoptosis and cell-cycle arrest in human lung cancer cells.Chin Med J (Engl). 2007,120(10):905-909.
[13] Yang L, Li N, Wang C, Yu Y, Yuan L, Zhang M, et al. Cyclin L2, a novel RNA polymerase II-associated cyclin, is involved in pre-mRNA splicing and induces apoptosis of human hepatocellular carcinoma cells. J Biol Chem 2004; 279:11639-11648.
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