小鼠心脏神经嵴细胞的生物学特性及其相关基因研究
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摘要
圆锥动脉干是在心脏胚胎发育时期连接动脉弓的动脉干和连接心室的圆锥部的总称。心脏圆锥动脉干缺损是圆锥动脉干发育障碍所造成的一类先天性心脏病，包括法洛四联症、大动脉转位、右室双出口、永存动脉干等多种导致紫绀和低氧血症的心脏复杂畸形，这类复杂心血管畸形约占先天性心脏病的30％。人类CTD的发病机制复杂，但近二十年来的研究发现提示，Connexin 43(Cx43)基因及心脏神经嵴细胞与心脏锥干部发育密切相关。心脏神经嵴细胞是从枕部神经嵴分化出来的一群细胞，这群细胞通过第3，4，6咽弓向原始心管迁移，最后停留在动脉干和动脉圆锥等部位分化为间充质细胞，主要参与心脏流出道隔及大血管的形成。研究发现，如果在迁移之前切除散发到第3、4、6咽弓的神经嵴细胞，就会出现永存动脉干、主动脉骑跨、右室双出口、主动脉弓畸型和室间隔缺损等心血管畸形，且切除的长度与畸形的种类相关，如切除长度大于两个体节可产生永存动脉干，切除长度小于两个体节则产生右室双流出道，由此可见，心脏神经嵴细胞对于心脏圆锥部的发育意义重大。Cx43是细胞缝隙连接基因家族的成员之一，近年的研究发现其与心血管发育密切相关。研究发现，Cx43基因剔除小鼠、过量表达Cx43的CMV43转基因小鼠和显性失活抑制Cx43组成的细胞间隙的信息交流的FC转基因小鼠均可见右室流出道畸形和梗阻，从而说明，精确的Cx43基因表达对于圆锥部的发育至关重要。在小鼠胚胎发育过程中，Cx43大量表达于迁移性神经嵴细胞之上(最早于ED9.5d即可见)，并参与形成心脏神经嵴细胞的缝隙连接。越来越多的研究提示Cx43可能通过调节心脏神经嵴的行为而间接影响心脏的形态发生。因此，本课题利用Cx43基因剔除(knockout，KO)小鼠模型结合日益发展的基因芯片技术进行研究，旨在研究Cx43基因对心脏神经嵴的诱导、发生、分离、迁移、分化的调控机制，进一步阐明Cx43影响心脏圆锥发育过程其可能的分子机制。
第一部分 小鼠心脏神经嵴细胞的体外培养与生物学特性研究
研究目的
体外培养和鉴定心脏神经嵴细胞，并探讨其增殖、迁移及分化等生物学特性。
材料与方法
成年2月龄C57／BL6小鼠交配，取ED8.5d小鼠胚胎枕中部至第3体节神经管，应用包含碱性纤维生长因子(bEGF)和表皮细胞生长因子(EGF)的无血清培养基培养，利用MTT法检测细胞增殖能力，利用流式细胞仪检测细胞周期，采用转录激活因子2α(AP-2α，Activator protein-2α)作为其生物学标记物，观察其增殖状况、细胞周期、迁移、分化等生物学特性。
结果
从胎鼠神经管中分离培养的细胞增殖旺盛，AP-2α表达阳性，细胞具有明显迁移特性，传代后以含血清培养基培养后能诱导分化成神经元和神经胶质细胞。
小结
1．采用无血清培养技术在体外培养可成功获得心脏神经嵴细胞；
2．体外培养的心脏神经嵴细胞增殖旺盛，具有迁移特性和多向潜能分化能力
第二部分 Cx43基因敲除鼠心脏神经嵴细胞的基因表达及验证
研究目的
研究Cx43基因敲除(Cx43 KO)小鼠胚胎心脏神经嵴细胞中基因表达谱的改变，筛选可能导致Cx43KO小鼠圆锥动脉干畸形的相关基因，并探讨相关机制。
材料与方法
以胎龄(embryonic day，ED)8.5天的Cx43KO和野生型(Cx43WT)鼠胚心脏神经嵴细胞为研究对象，分别提取总RNA，逆转录成cDNA；并在体外转录为cRNA，同时进行生物素标记及片段化；再与Affymetrix-430 2.0基因芯片进行杂交。杂交信号经扫描后，应用相关生物信息软件分析基因表达情况。选取部分差异基因应用RT-PCR方法验证基因芯片结果的可靠性。
结果
1、与WT组相比，Cx43KO组中表达上调2倍以上的基因共有288个，表达下调2倍以上的基因有124个。这些差异基因主要涉及转录调控、细胞运动、细胞周期及代谢等多种功能，其中与转录调控相关的基因数改变最多。
2、PT-PCR结果与基因芯片结果相符，Affymetrix基因芯片结果能够很好的反映Cx43敲除鼠心脏神经嵴细胞与野生型鼠心脏神经嵴细胞的差异基因表达。
小结
利用基因芯片技术初步筛选出Cx43KO鼠心脏神经嵴细胞中多个差异基因，这些差异基因主要涉及转录调控、细胞运动、细胞周期及代谢等多种功能，其中转录调控相关基因数改变最多，提示Cx43可能主要通过转录调控等途径影响心脏神经嵴细胞的诱导、发生、分离、迁移等生物学功能并最终影响心脏圆锥部的发育。
Conotruncus arteriosus is the conotruncal position including collected truncus arteriosus and partial ventricle involved. Conotruncal defects (CTD) is a kind of complicated heart disease with cyanosis and hypoxemia, including tetralogy of Fallot (TOF), transposition of the great arteries(TGA), double-outlet right ventricle (DORV), persistent truncus arteriosus (PTA), which accounts for 30% of congenital heart disease. Although the mechanism of human conotruncal defects is complicated, studies have shown that connexin43 and cardiac neural crest cells (CNCCs) closely related to conotruncal development. CNCCs migrate from 3, 4, 6 pharyngeal gland to original heart tube, localize at truncus arteriosus and conotruncal region, differentiate into mesenchymal cells that give rise to the formation of outflow tract septum and blood vessel. Heart malformation, such as PTA, DORV, VSD and aortic arch malformation, were detected when neural crest were taken out before they migrated into 3, 4, 6 pharyngeal gland. Interestingly, the types of malformation were related with the length of neural crest destroyed; PTA was detected if the length exceeds two somites, while DORV would be detected if the length less than two somites. These results indicate that CNCCs are very important to the conotruncal development.
Cx43 is one member of connexin gene family, which is proved to be closely related to conotruncal development. Right ventricular outflow tract malformatin and obstruction were found in dysfunction of Cx43 gap junction such as Cx43 KO mice, CMV43 mice and FC mice, which indicates appropriate expression of Cx43 plays a very important role in conotruncal development. In the process of mouse embryo development, Cx43 expressed in CNCCs during migration (as early as at ED9.5d), which also take part in gap junction formation of CNCCs. Lots of studies indicate that Cx43 may affect heart development through regulating the biological characteristics of CNCCs.
Hence, in this study we used Cx43KO mouse and microarray technology to explore the role of Cx43 in affecting the induction, generation, delamination, migration and differentiation of cardiac neural crest cells, and therefore further reveal the molecular mechanisms of the conotruncal malformations in Cx43KO mice.
Part I Isolation, cultivation and biological characteristics analysis of cardiac neural crest cells of embryonic mice
Objective
To establish the in-vitro culture methods of cardiac neural crest cells of embryonic mice and identify their biological properties, such as proliferation capacity, migration and differentiation potential.
Methods
Neural tubes isolated from the region between midotic placode and third somite of mouse embryo at ED 8.5d were cultured in DMEM/F12 serum-free medium containing basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The cell cycle of CNCCs was analyzed with flow cytometry, the proliferation capability was determined by MTT method, AP-2α expression was detected by immunocytochemistry as a biological marker of cardiac neural crest cells. The features of migration, multi-directional differentiation were observed as well.
Results
The MTT and cell cycle analysis indicated that cells proliferated actively. AP-2α expressed abundantly in the cultured neural crest cells, which was of the ability of migration and was able to differentiate into neurons and astrocytes as well.
Conclusions
1. The cardiac neural crest cells of mouse embryo can be successfully cultured in vitro.
2. These cultured cells have the ability of proliferation, migration and the potential of multi-directional differentiation.
Part II Differentially expressed genes in the Cx43 knockout cardiac neural crest cells of mice
Objective
To investigate changes of gene expression in the cardiac neural crest cells in Cx43 knockout mouse embryo, and to elucidate the genes involving in the pathogenesis of conotruncal malformation in Cx43 knockout mouse.
Methods
The cDNA was retrotranscribed from RNA extracted from cardiac neural crest cells of both Cx43 knockout and Cx43 wildtype mouse embryos on ED8.5d. The biotin-labeled cRNA derived from the transcription of cDNA was fragmented as probes. The probes were hybridized with Affymetrix Mouse Genome 430 2.0 Array. Gene Array Scanner was used to screen the signals of hybridization and the expression of genes was detected. RT-PCR was utilized to confirm the changes of partial genes that were detected by Affymetrix Mouse Genome 430 2.0 Array.
Results
1. Among the differently expressed genes, there were 288 upregulated and 124 downregulated in CNCCs of Cx43 knockout mice as compared with those of Cx43 wild type mice. Functions of proteins encoded by the altered genes encompassed all functional categories, with largest percentage in genes involved in regulation of transcription, cell motility, cell cycle and metabolism.
2. The data of RT-PCR indicate that cDNA Array results accurately reflect changes in gene expression patterns in cardiac neural crests of Cx43KO mouse as compared with those of WT mouse.
Conclusions
By cDNA array technology, we compare changes in gene expression between CNCCs of Cx43 KO mouse and those of WT mouse, in which genes related to regulation of transcription changed most, indicating Cx43 may afffect the function of cardiac neural crest cells through regulation of transcription.
第一部分 小鼠心脏神经嵴细胞的体外培养与生物学特性研究
研究目的
体外培养和鉴定心脏神经嵴细胞，并探讨其增殖、迁移及分化等生物学特性。
材料与方法
成年2月龄C57／BL6小鼠交配，取ED8.5d小鼠胚胎枕中部至第3体节神经管，应用包含碱性纤维生长因子(bEGF)和表皮细胞生长因子(EGF)的无血清培养基培养，利用MTT法检测细胞增殖能力，利用流式细胞仪检测细胞周期，采用转录激活因子2α(AP-2α，Activator protein-2α)作为其生物学标记物，观察其增殖状况、细胞周期、迁移、分化等生物学特性。
结果
从胎鼠神经管中分离培养的细胞增殖旺盛，AP-2α表达阳性，细胞具有明显迁移特性，传代后以含血清培养基培养后能诱导分化成神经元和神经胶质细胞。
小结
1．采用无血清培养技术在体外培养可成功获得心脏神经嵴细胞；
2．体外培养的心脏神经嵴细胞增殖旺盛，具有迁移特性和多向潜能分化能力
第二部分 Cx43基因敲除鼠心脏神经嵴细胞的基因表达及验证
研究目的
研究Cx43基因敲除(Cx43 KO)小鼠胚胎心脏神经嵴细胞中基因表达谱的改变，筛选可能导致Cx43KO小鼠圆锥动脉干畸形的相关基因，并探讨相关机制。
材料与方法
以胎龄(embryonic day，ED)8.5天的Cx43KO和野生型(Cx43WT)鼠胚心脏神经嵴细胞为研究对象，分别提取总RNA，逆转录成cDNA；并在体外转录为cRNA，同时进行生物素标记及片段化；再与Affymetrix-430 2.0基因芯片进行杂交。杂交信号经扫描后，应用相关生物信息软件分析基因表达情况。选取部分差异基因应用RT-PCR方法验证基因芯片结果的可靠性。
结果
1、与WT组相比，Cx43KO组中表达上调2倍以上的基因共有288个，表达下调2倍以上的基因有124个。这些差异基因主要涉及转录调控、细胞运动、细胞周期及代谢等多种功能，其中与转录调控相关的基因数改变最多。
2、PT-PCR结果与基因芯片结果相符，Affymetrix基因芯片结果能够很好的反映Cx43敲除鼠心脏神经嵴细胞与野生型鼠心脏神经嵴细胞的差异基因表达。
小结
利用基因芯片技术初步筛选出Cx43KO鼠心脏神经嵴细胞中多个差异基因，这些差异基因主要涉及转录调控、细胞运动、细胞周期及代谢等多种功能，其中转录调控相关基因数改变最多，提示Cx43可能主要通过转录调控等途径影响心脏神经嵴细胞的诱导、发生、分离、迁移等生物学功能并最终影响心脏圆锥部的发育。
Conotruncus arteriosus is the conotruncal position including collected truncus arteriosus and partial ventricle involved. Conotruncal defects (CTD) is a kind of complicated heart disease with cyanosis and hypoxemia, including tetralogy of Fallot (TOF), transposition of the great arteries(TGA), double-outlet right ventricle (DORV), persistent truncus arteriosus (PTA), which accounts for 30% of congenital heart disease. Although the mechanism of human conotruncal defects is complicated, studies have shown that connexin43 and cardiac neural crest cells (CNCCs) closely related to conotruncal development. CNCCs migrate from 3, 4, 6 pharyngeal gland to original heart tube, localize at truncus arteriosus and conotruncal region, differentiate into mesenchymal cells that give rise to the formation of outflow tract septum and blood vessel. Heart malformation, such as PTA, DORV, VSD and aortic arch malformation, were detected when neural crest were taken out before they migrated into 3, 4, 6 pharyngeal gland. Interestingly, the types of malformation were related with the length of neural crest destroyed; PTA was detected if the length exceeds two somites, while DORV would be detected if the length less than two somites. These results indicate that CNCCs are very important to the conotruncal development.
Cx43 is one member of connexin gene family, which is proved to be closely related to conotruncal development. Right ventricular outflow tract malformatin and obstruction were found in dysfunction of Cx43 gap junction such as Cx43 KO mice, CMV43 mice and FC mice, which indicates appropriate expression of Cx43 plays a very important role in conotruncal development. In the process of mouse embryo development, Cx43 expressed in CNCCs during migration (as early as at ED9.5d), which also take part in gap junction formation of CNCCs. Lots of studies indicate that Cx43 may affect heart development through regulating the biological characteristics of CNCCs.
Hence, in this study we used Cx43KO mouse and microarray technology to explore the role of Cx43 in affecting the induction, generation, delamination, migration and differentiation of cardiac neural crest cells, and therefore further reveal the molecular mechanisms of the conotruncal malformations in Cx43KO mice.
Part I Isolation, cultivation and biological characteristics analysis of cardiac neural crest cells of embryonic mice
Objective
To establish the in-vitro culture methods of cardiac neural crest cells of embryonic mice and identify their biological properties, such as proliferation capacity, migration and differentiation potential.
Methods
Neural tubes isolated from the region between midotic placode and third somite of mouse embryo at ED 8.5d were cultured in DMEM/F12 serum-free medium containing basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF). The cell cycle of CNCCs was analyzed with flow cytometry, the proliferation capability was determined by MTT method, AP-2α expression was detected by immunocytochemistry as a biological marker of cardiac neural crest cells. The features of migration, multi-directional differentiation were observed as well.
Results
The MTT and cell cycle analysis indicated that cells proliferated actively. AP-2α expressed abundantly in the cultured neural crest cells, which was of the ability of migration and was able to differentiate into neurons and astrocytes as well.
Conclusions
1. The cardiac neural crest cells of mouse embryo can be successfully cultured in vitro.
2. These cultured cells have the ability of proliferation, migration and the potential of multi-directional differentiation.
Part II Differentially expressed genes in the Cx43 knockout cardiac neural crest cells of mice
Objective
To investigate changes of gene expression in the cardiac neural crest cells in Cx43 knockout mouse embryo, and to elucidate the genes involving in the pathogenesis of conotruncal malformation in Cx43 knockout mouse.
Methods
The cDNA was retrotranscribed from RNA extracted from cardiac neural crest cells of both Cx43 knockout and Cx43 wildtype mouse embryos on ED8.5d. The biotin-labeled cRNA derived from the transcription of cDNA was fragmented as probes. The probes were hybridized with Affymetrix Mouse Genome 430 2.0 Array. Gene Array Scanner was used to screen the signals of hybridization and the expression of genes was detected. RT-PCR was utilized to confirm the changes of partial genes that were detected by Affymetrix Mouse Genome 430 2.0 Array.
Results
1. Among the differently expressed genes, there were 288 upregulated and 124 downregulated in CNCCs of Cx43 knockout mice as compared with those of Cx43 wild type mice. Functions of proteins encoded by the altered genes encompassed all functional categories, with largest percentage in genes involved in regulation of transcription, cell motility, cell cycle and metabolism.
2. The data of RT-PCR indicate that cDNA Array results accurately reflect changes in gene expression patterns in cardiac neural crests of Cx43KO mouse as compared with those of WT mouse.
Conclusions
By cDNA array technology, we compare changes in gene expression between CNCCs of Cx43 KO mouse and those of WT mouse, in which genes related to regulation of transcription changed most, indicating Cx43 may afffect the function of cardiac neural crest cells through regulation of transcription.
引文
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44. Otto A, Schmidt C, Patel K. Pax3 and Pax7 expression and regulation in the avian embryo. Anat Embryol (Berl). 2006, 211(4): 293-310.
45. Fukiishi, Y. and Morriss-Kay, G. M. Migration of cranial neural crest cells to the pharyngeal arches and heart in rat embryos. Cell Tissue Res. 1992, 268(1): 1-8.
46. Franz T. Persistent truncus arteriosus in the Splotch mutant mouse. Anat Embryol 1989, 180(5): 457-464.
47. Daston G, Lamar E, Olivier M, et al. Pax3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 1996, 122(3): 1017-1027.
48. Yang X-M, Vogan K, Gros P, Park M. Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice. Development. 1996, 122(7): 2163-217
49. Takahashi Y. Organization of the spina bifida neural tube in Splotch (Pax3 defective) mouse embryos. Dev Growth Diff. 1996, 38(1): 23-31.
50. Moase CE, Trasler DG. N-CAM alterations in splotch neural tube defect mouse embryos. Development. 1991, 113(3): 1049-1058.
51. Wegner M. From head to toes: The multiple facets of Sox proteins. Nucleic Acids Res. 1999, 27 (6): 1409-1420.
52. Wilson M, Koopman P. Matching SOX: Partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opi n Genet Dev. 2002, 12 (4) : 441-446.
53. Dutton KA, Pauliny A, Lopes SS, et al. Zebrafish colourless encodes sox10 and specifies nonectmesenchymal neural crest fates. Development. 2001, 128(21): 4113-4125.
54. Kamachi, Y, Uchikawa, M, Kondoh H. Pairing SOX off with partners in the regulation of embryonic development. Trends Genet. 2000, 16(4): 182-187.
55. Southard-Smith, EM, Kos L, Pavan WJ. SoxlO mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat. Genet. 1998, 18(1): 60-64.
56. Britsch S, Goerich DE, Riethmacher D, et al. The transcription factor SoxlO is a key regulator of peripheral glial development. Genes Dev. 2001, 15(1): 66-78.
57. Potterf SB, Furumura M, Dunn KJ, et al. Transciption factor hierachy in Waardenburg syndrome: regulation of MITF expression by SoxlO and Pax3. Hum Genet. 2000, 107(1): 1-6.
58. Tachibana M. A cascade of genes related to Waardenburg syndrome. J Investig Dermatol Symo Pro. 1999, 4(2): 126-129.
59. Akiyama H, Chaboissier MC, Behringe, RR, et al. Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa. Proc Natl Acad Sci USA. 2004, 101(17): 6502-6507.
60. Hanna LA, Foreman RK, Tarasenko IA, et al. Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev. 2002, 16(20): 2650-2661.
61. Pohl BS, Knochel W. Overexpression of the transcriptional repressor FoxD3 prevents neural crest formation in Xenopus embryos. Mech Dev. 2001, 103(1): 93-106.
62. Pietri T, Eder O, Breau MA, Topilko P, et al. Conditional β1-integrin gene deletion in neural crest cells causes severe developmental alternations of the peripheral nervous system. Development. 2004, 131(16): 3871-3883.
63. Nakagawa S, Takeichi M. Neural crest emigration from the neural tube depends on regulated cadherin expression. Development. 1998, 125(15): 2963-2971.
64. Bonstein L, Elias S, Frank D. Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos. Dev Biol. 1998,193(2): 156-168.
65. Garcia-Castro MI, Marcelle C, Bronner-Fraser M. Ectodermal Wnt function as a neural crest inducer. Science. 2002, 297(5582): 848-851.
66. Liem KF, Tremml G, Roelink H, et al. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell. 1995, 82(6): 969-979.
67. Marchant L, Linker C, Ruiz P, et al. The inductive properties of mesoderm suggest that the neural crestcells are specified by a BMP gradient. Dev Biol. 1998,198(2): 319-329.
68. Monsoro-Burq AH, Fletcher RB, Harland RM. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development 2003, 130(14): 3111-3124.
69. Endo Y, Osumi N, Wakamatsu Y. Bimodal function of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development. 2002, 129(4): 863-873.
70. Glavic A, Silva F, Aybar MJ, et al. Interplay between Notch signaling and the homeoprotein Xirol is required for neural crest induction in Xenopus embryos. Development. 2004, 131(2): 347-359.
71.Heeg-Truesdell E, LaBonne C. A slug, a fox, a pair of Sox: Transcriptional responses to neural crest inducing signals. Birth Defects Res (Part C). 2004, 72(2): 124-139.
72. Cheung M, Chaboissier MC, Mynett A, et al. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev Cell. 2005, 8(2): 179-92.
73. LaBonne C, Bronner-Fraser M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev Biol. 2000, 221(1): 195-205.
74. Lang D, Epstein JA. Sox10 and Pax3 physically inter act to mediate activation of a conserved c-RET enhancer. Hum Mol Genet. 2003, 12(8): 937-945.
75. Borycki AG, Li J, Jin F, et al. Pax3 functions in cell survival and in pax7 regulation. Development. 1999, 126(8): 1665-1674.
76. Mansouri A, Pla P, Larue L, et al. Pax3 acts cell autonomously in the neural tube and somites by controlling cell surface properties. Development. 2001, 128(11): 1995-2005.
77. Wiggan O, Hamel PA.. Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/non-canonical Wnt-signaling cascade. J Cell Sci. 2002, 115(3): 531-541.
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3. Baker CV, Bronner-Fraser M. The origins of the neural crest. Part Ⅰ: embryonic induction. Mech of Dev. 1997,69(1-2): 3-11.
4. Baker CV, Bronner-Fraser M. The origins of the neural crest. Part Ⅱ: an evolutionary perspective. Mech Dev. 1997,69(1-2): 13-29.
5. Sellecka MA, Bronner-Fraser M. Avian neural crest cell fate decisions: a divisible signal mediates induction of neural crest by the ectoderm. Int J Dev Neurosci. 2000, 18(7): 621-627.
6. Kleber M, Lee HY, Wurdak H, et al. Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling. J Cell Biol. 2005, 169(2): 309-320.
7. LaBonne C, Bronner-Fraser M. Neural crest cell induction in Xenopus: Evidence for a two-signal model. Development. 1998,125(13): 2403-2414.
8. Barembaum M, Moreno T, Labonne C, et al. Noelin-1 is a secreted glycoprotein involved in generation of neural crest. Nature Cell Biol. 2002, 2(2): 219-225.
9. Gammill LS, Bronner-Fraser M. Genomic analysis of neural crest induction. Development. 2002, 129(24): 5731-5741
10. Mayor, Gurrero R, Martinez. C. Role of FGF and Noggin in neural crest induction. Dev Biol. 1997, 189(1):1-12.
11. Monsoro-Burq AH, Fletcher RB, Harland RM, et al. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development. 2003,130(14): 3111-24.
12. Nakagawa S, Takeichi M. Neural crest emigration from the neural tube depends on regulated cadherin expression. Development. 1998, 125(15): 2963-2971.
13. Bonstein L, Elias S, Frank D. Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos. Dev Biol. 1998,193(2): 156-168.
14. Garcia-Castro MI, Marcelle C, Bronner-Fraser M. Ectodermal Wnt function as a neural crest inducer. Science. 2002, 297(5582): 848-851.
15. Liem KF, Tremml G, Roelink H, et al. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell. 1995, 82(6): 969-979.
16. Marchant L, Linker C, Ruiz P, et al. The inductive properties of mesoderm suggest that the neural crestcells are specified by a BMP gradient. Dev. Biol. 1998,198(2): 319-329.
17. Monsoro-Burq AH, Fletcher RB, Harland RM. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development. 2003, 130(14): 3111-3124.
18. Endo Y, Osumi N, Wakamatsu Y. Bimodal function of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development. 2002, 129(4): 863-873.
19. Glavic A, Silva F, Aybar MJ, et al. Interplay between Notch signaling and the homeoprotein Xirol is required for neural crest induction in Xenopus embryos. Development. 2004, 131(2): 347-359.
20. Heeg-Truesdell E, LaBonne C. A slug, a fox, a pair of Sox: Transcriptional responses to neural crest inducing signals. Birth Defects Res (Part C). 2004, 72(2): 124-139.
21. Cheung M, Chaboissier MC, Mynett A, et al. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev Cell. 2005, 8(2): 179-92.
22. LaBonne C, Bronner-Fraser M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev Biol. 2000, 221(1): 195-205.
23. Lang D, Epstein JA. Sox 10 and Pax3 physically inter act to mediate activation of a conserved c-RET enhancer. Hum Mol Genet. 2003, 12(8): 937-945.
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42. Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor Snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000, 2(1): 76-83.
43. Luo T, Lee YH, Saint-Jeannet JP, et al. Induction of neural crest in Xenopus by transcription factor AP2α. Proc Natl Acad Sci USA. 2003, 100(2): 532-537.
44. Otto A, Schmidt C, Patel K. Pax3 and Pax7 expression and regulation in the avian embryo. Anat Embryol (Berl). 2006, 211(4): 293-310.
45. Fukiishi, Y. and Morriss-Kay, G. M. Migration of cranial neural crest cells to the pharyngeal arches and heart in rat embryos. Cell Tissue Res. 1992, 268(1): 1-8.
46. Franz T. Persistent truncus arteriosus in the Splotch mutant mouse. Anat Embryol 1989, 180(5): 457-464.
47. Daston G, Lamar E, Olivier M, et al. Pax3 is necessary for migration but not differentiation of limb muscle precursors in the mouse. Development 1996, 122(3): 1017-1027.
48. Yang X-M, Vogan K, Gros P, Park M. Expression of the met receptor tyrosine kinase in muscle progenitor cells in somites and limbs is absent in Splotch mice. Development. 1996, 122(7): 2163-217
49. Takahashi Y. Organization of the spina bifida neural tube in Splotch (Pax3 defective) mouse embryos. Dev Growth Diff. 1996, 38(1): 23-31.
50. Moase CE, Trasler DG. N-CAM alterations in splotch neural tube defect mouse embryos. Development. 1991, 113(3): 1049-1058.
51. Wegner M. From head to toes: The multiple facets of Sox proteins. Nucleic Acids Res. 1999, 27 (6): 1409-1420.
52. Wilson M, Koopman P. Matching SOX: Partner proteins and co-factors of the SOX family of transcriptional regulators. Curr Opi n Genet Dev. 2002, 12 (4) : 441-446.
53. Dutton KA, Pauliny A, Lopes SS, et al. Zebrafish colourless encodes sox10 and specifies nonectmesenchymal neural crest fates. Development. 2001, 128(21): 4113-4125.
54. Kamachi, Y, Uchikawa, M, Kondoh H. Pairing SOX off with partners in the regulation of embryonic development. Trends Genet. 2000, 16(4): 182-187.
55. Southard-Smith, EM, Kos L, Pavan WJ. SoxlO mutation disrupts neural crest development in Dom Hirschsprung mouse model. Nat. Genet. 1998, 18(1): 60-64.
56. Britsch S, Goerich DE, Riethmacher D, et al. The transcription factor SoxlO is a key regulator of peripheral glial development. Genes Dev. 2001, 15(1): 66-78.
57. Potterf SB, Furumura M, Dunn KJ, et al. Transciption factor hierachy in Waardenburg syndrome: regulation of MITF expression by SoxlO and Pax3. Hum Genet. 2000, 107(1): 1-6.
58. Tachibana M. A cascade of genes related to Waardenburg syndrome. J Investig Dermatol Symo Pro. 1999, 4(2): 126-129.
59. Akiyama H, Chaboissier MC, Behringe, RR, et al. Essential role of Sox9 in the pathway that controls formation of cardiac valves and septa. Proc Natl Acad Sci USA. 2004, 101(17): 6502-6507.
60. Hanna LA, Foreman RK, Tarasenko IA, et al. Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo. Genes Dev. 2002, 16(20): 2650-2661.
61. Pohl BS, Knochel W. Overexpression of the transcriptional repressor FoxD3 prevents neural crest formation in Xenopus embryos. Mech Dev. 2001, 103(1): 93-106.
62. Pietri T, Eder O, Breau MA, Topilko P, et al. Conditional β1-integrin gene deletion in neural crest cells causes severe developmental alternations of the peripheral nervous system. Development. 2004, 131(16): 3871-3883.
63. Nakagawa S, Takeichi M. Neural crest emigration from the neural tube depends on regulated cadherin expression. Development. 1998, 125(15): 2963-2971.
64. Bonstein L, Elias S, Frank D. Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos. Dev Biol. 1998,193(2): 156-168.
65. Garcia-Castro MI, Marcelle C, Bronner-Fraser M. Ectodermal Wnt function as a neural crest inducer. Science. 2002, 297(5582): 848-851.
66. Liem KF, Tremml G, Roelink H, et al. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell. 1995, 82(6): 969-979.
67. Marchant L, Linker C, Ruiz P, et al. The inductive properties of mesoderm suggest that the neural crestcells are specified by a BMP gradient. Dev Biol. 1998,198(2): 319-329.
68. Monsoro-Burq AH, Fletcher RB, Harland RM. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development 2003, 130(14): 3111-3124.
69. Endo Y, Osumi N, Wakamatsu Y. Bimodal function of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development. 2002, 129(4): 863-873.
70. Glavic A, Silva F, Aybar MJ, et al. Interplay between Notch signaling and the homeoprotein Xirol is required for neural crest induction in Xenopus embryos. Development. 2004, 131(2): 347-359.
71.Heeg-Truesdell E, LaBonne C. A slug, a fox, a pair of Sox: Transcriptional responses to neural crest inducing signals. Birth Defects Res (Part C). 2004, 72(2): 124-139.
72. Cheung M, Chaboissier MC, Mynett A, et al. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev Cell. 2005, 8(2): 179-92.
73. LaBonne C, Bronner-Fraser M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev Biol. 2000, 221(1): 195-205.
74. Lang D, Epstein JA. Sox10 and Pax3 physically inter act to mediate activation of a conserved c-RET enhancer. Hum Mol Genet. 2003, 12(8): 937-945.
75. Borycki AG, Li J, Jin F, et al. Pax3 functions in cell survival and in pax7 regulation. Development. 1999, 126(8): 1665-1674.
76. Mansouri A, Pla P, Larue L, et al. Pax3 acts cell autonomously in the neural tube and somites by controlling cell surface properties. Development. 2001, 128(11): 1995-2005.
77. Wiggan O, Hamel PA.. Pax3 regulates morphogenetic cell behavior in vitro coincident with activation of a PCP/non-canonical Wnt-signaling cascade. J Cell Sci. 2002, 115(3): 531-541.
1. Morrison SJ. Neuronal potential and lineage determination by neural stem cells. Curr Opin Cell Biol. 2001, 13(6): 666-672.
2. Bronner-Fraser M. Molecular analysis of neural crest formation. J Physiol Paris. 2002,96(1-2): 3-8.
3. Baker CV, Bronner-Fraser M. The origins of the neural crest. Part Ⅰ: embryonic induction. Mech of Dev. 1997,69(1-2): 3-11.
4. Baker CV, Bronner-Fraser M. The origins of the neural crest. Part Ⅱ: an evolutionary perspective. Mech Dev. 1997,69(1-2): 13-29.
5. Sellecka MA, Bronner-Fraser M. Avian neural crest cell fate decisions: a divisible signal mediates induction of neural crest by the ectoderm. Int J Dev Neurosci. 2000, 18(7): 621-627.
6. Kleber M, Lee HY, Wurdak H, et al. Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling. J Cell Biol. 2005, 169(2): 309-320.
7. LaBonne C, Bronner-Fraser M. Neural crest cell induction in Xenopus: Evidence for a two-signal model. Development. 1998,125(13): 2403-2414.
8. Barembaum M, Moreno T, Labonne C, et al. Noelin-1 is a secreted glycoprotein involved in generation of neural crest. Nature Cell Biol. 2002, 2(2): 219-225.
9. Gammill LS, Bronner-Fraser M. Genomic analysis of neural crest induction. Development. 2002, 129(24): 5731-5741
10. Mayor, Gurrero R, Martinez. C. Role of FGF and Noggin in neural crest induction. Dev Biol. 1997, 189(1):1-12.
11. Monsoro-Burq AH, Fletcher RB, Harland RM, et al. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development. 2003,130(14): 3111-24.
12. Nakagawa S, Takeichi M. Neural crest emigration from the neural tube depends on regulated cadherin expression. Development. 1998, 125(15): 2963-2971.
13. Bonstein L, Elias S, Frank D. Paraxial-fated mesoderm is required for neural crest induction in Xenopus embryos. Dev Biol. 1998,193(2): 156-168.
14. Garcia-Castro MI, Marcelle C, Bronner-Fraser M. Ectodermal Wnt function as a neural crest inducer. Science. 2002, 297(5582): 848-851.
15. Liem KF, Tremml G, Roelink H, et al. Dorsal differentiation of neural plate cells induced by BMP-mediated signals from epidermal ectoderm. Cell. 1995, 82(6): 969-979.
16. Marchant L, Linker C, Ruiz P, et al. The inductive properties of mesoderm suggest that the neural crestcells are specified by a BMP gradient. Dev. Biol. 1998,198(2): 319-329.
17. Monsoro-Burq AH, Fletcher RB, Harland RM. Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals. Development. 2003, 130(14): 3111-3124.
18. Endo Y, Osumi N, Wakamatsu Y. Bimodal function of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development. Development. 2002, 129(4): 863-873.
19. Glavic A, Silva F, Aybar MJ, et al. Interplay between Notch signaling and the homeoprotein Xirol is required for neural crest induction in Xenopus embryos. Development. 2004, 131(2): 347-359.
20. Heeg-Truesdell E, LaBonne C. A slug, a fox, a pair of Sox: Transcriptional responses to neural crest inducing signals. Birth Defects Res (Part C). 2004, 72(2): 124-139.
21. Cheung M, Chaboissier MC, Mynett A, et al. The transcriptional control of trunk neural crest induction, survival, and delamination. Dev Cell. 2005, 8(2): 179-92.
22. LaBonne C, Bronner-Fraser M. Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration. Dev Biol. 2000, 221(1): 195-205.
23. Lang D, Epstein JA. Sox 10 and Pax3 physically inter act to mediate activation of a conserved c-RET enhancer. Hum Mol Genet. 2003, 12(8): 937-945.