神经管缺陷的病因及发病机理的基础研究
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摘要
背景:神经管畸形的发生是由遗传因素与环境因素共同作用产生的。平面细胞极性(planar cell polarity, PCP)途径对脊椎动物神经胚形成非常重要,而PCP基因表达量及产物的不对称分布将影响PCP。该途径中基因的任何突变都可能导致神经管不能闭合,其表型与人类的颅脊柱裂相似。但是,环境因素是否影响以及如何影响PCP途径基因的时空表达到目前为止仍然不清楚。
目的:研究维甲酸对胎鼠Vangl1及Vangl2基因表达的时空特征的影响。
方法:全反式维甲酸橄榄油混悬液按120 mg/kg在BALB/C小鼠怀孕第9.5天(E9.5)(G1组)或E10.5(G2组)灌胃。两组的对照组(G1c、G2c)在相同时期仅用等量纯橄榄油灌胃。分别取E10.5、E11.5、E13.5、E15.5、E17.5、E19.5胎鼠,Vangl1及Vangl2基因表达量采用逆转录酶PCR(RT-PCR)检测,其时空表达采用全胚胎原位杂交(whole-mount in situ hybridization, WISH)检测。
结果:活产NTDs的发生率及颅面部NTDs发生率G1组(100%、25.6%)均高于G2组(78.2%、5.7%),P均< 0.05。正常情况下Vangl1及Vangl2基因在整个神经胚形成过程中都有强表达。而G1组同期对照组比较,从胎鼠的脑到后神经孔Vangl1及Vangl2基因表达显著下调(P均< 0.05)。G2组则不同,二基因表达在全胚胎(从E11.5到E13.5)及神经管脊柱区(从E15.5到E19.5)显著下调并维持低表达水平,但在神经管的颅区(E15.5到E19.5)仅中度下调(P均< 0.05)。
结论:结果提示,维甲酸诱导的神经管畸形的发生可能与Vangl1及Vangl2基因转录子下调有关。
背景:神经管缺陷(neural tube defects, NTDs)是由环境危险因素与遗传危险因素间复杂的相互作用引起的。其潜在的发病机理仍然不清楚。从遗传和环境角度看,叶酸代谢相关基因都是NTDs的令人关注的候选基因。目前叶酸代谢相关基因间以及基因与环境间交互作用的研究较少,已有的文献间还存在相互矛盾。
目的:通过对叶酸代谢相关基因的单核苷酸多态性(single nucleotide polymorphism, SNPs)与多重环境危险因子交互作用的关联分析,寻找NTDs致病基因及环境危险因素。
方法:收集NTDs流产胎儿组织标本或者患者血标本(共117例)以及其双亲的血标本(共216例),记录围孕期补充叶酸、妊娠糖尿病、孕期服药史等情况。采用CEQ 8800系统进行多重SNP分析,对所有样本叶酸代谢相关的12个基因共28个SNPs测序。这些基因是:叶酸受体1及2、溶质载体家族19成员1、运钴胺蛋白II、亚甲四氢叶酸脱氢酶1、丝氨酸羟甲基转移酶1、5,10-亚甲基四氢叶酸还原酶、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶还原酶、甜菜碱同型半胱氨酸甲基转移酶、胱硫醚β合酶和内皮一氧化氮合酶3。
通过病例-双亲对照研究(case-parent control study)及传递/不平衡检验(transmission/ disequilibrium tests, TDT),分析SNPs与环境危险因子(孕期补充叶酸、妊娠糖尿病和孕期服药史)交互作用对NTDs发病的影响。
结果:亚甲基四氢叶酸还原酶(MTHFR)rs1801133与NTDs的关联具有显著性意义(P < 0.05),而且环境风险因子(未补充叶酸、妊娠糖尿病)对NTDs的发生起增效作用;而甜菜碱同型半胱氨酸甲基转移酶(BHMT)rs3733890仅在未补充叶酸层与NTDs存在连锁不平衡(P < 0.05),基因型本身并不能单独导致疾病;而其他基因的SNPs与NTDs的发生没有显著性关联(P均> 0.05)。
结论: MTHFR rs1801133是NTDs的危险因子,而BHMT rs3733890不是NTDs独立的危险因子。未来尚需要对更大的样本进行基因与基因、基因与环境交互作用的研究。
背景:骨龄评估对内分泌障碍与生长落后等疾病的诊断与治疗、预测成人身高等有重要指导意义。常用的骨龄评估方法中,Greulich-Pyle法具有主观性,而Tanner-Whitehouse(TW3)法操作起来较为复杂。十多年来人们一直在探索自动化骨龄评估(automatic bone age assessment, ABAA),但兴趣区(regions of interest, ROI)分割与边界的识别仍然是目前限制ABAA的富有挑战性的难题。
目的:应用两种新的算法即粒子群优化(PSO)及人工神经网络(ANN)以提高自动化骨龄评估的准确性和实用性。
方法:建立基于目标的ROI。按照Tanner-Whitehouse (TW3)法将ROI分为RUS(包括尺桡骨及掌指骨)ROI及腕骨ROI。每个兴趣区提取5项特征(包括大小、形态及融合状态)输入人工神经网络(artificial neural networks, ANN)分类器,ANN建立在前馈的多层网络基础上,并以反向传播算法规则训练ANN以分别处理RUS及腕骨特征。约1,046份左手及腕的数字X光片被随机分成两部分,一半用以训练ANN,另一半用以ABAA,而之前全部采用修订的Greulich-Pyle法人工判读骨龄。
结果:人工阅读骨龄与ABAA比较,RUS骨龄95%的可信区间是-0.010岁–0.084岁,腕骨骨龄95%的可信区间是-0.055岁–0.015岁。RUS及腕骨自动化骨龄评估结果与Greulich-Pyle法比较均具有很高的一致率(分别为97.9%与96.5%),变异系数相似(3.4与3.7),并且与人工阅读相比均无显著性差异(t=1.563与-1.123,P均> 0.05)。
结论:PSO对图像分割与特征的提取更为有效和准确。该ANN经训练后能更全面地处理影像特征信息,准确判断骨龄。基于智能算法的ABAA系统成功地应用于骨龄0–18岁所有病例。
Objective: This study reported the effects of retinoic acid upon the spatiotemporal expressions of Vangl1 and Vangl2 in mouse fetuses.
Material and method: Single dose of 120 mg/kg body weight of all trans-retinoic acid suspended in olive oil was administered intragastrically to each pregnant BALB/C mice on embryonic day (E) 9.5 (group 1, G1) or E10.5 (group 2, G2); mice treated with pure olive oil on E9.5 or E10.5 served as control groups. The expressions of Vangl1 and Vangl2 in fetuses were investigated by reverse transcriptase PCR (RT-PCR) and their spatial and temporal expressions were detected by whole-mount in situ hybridization (WISH) on E10.5, E11.5, E13.5, E15.5, E17.5 and E19.5 respectively.
Results: The study indicated that the incidence of NTDs in live birth and craniofacial NTDs rate were significantly higher in G1 (100% and 25.6%) than that in G2 (78.2% and 5.7%), both P < 0.05. Vangl1 and Vangl2 were strongly expressed throughout neurulation in embryos of control groups. G1 embryos exhibited a dramatic downregulation of Vangl1 and Vangl2 expressions from cranial region to posterior neuropore compared with the control group of G1 (all P < 0.05). In contrast, the both transcripts in G2 embryos were significantly downregulated and weakly expressed in whole embryos from E11.5 to E13.5 and in the spinal region of neural tube from E15.5 to E19.5, but moderately downregulated in the cranial region of neural tube from E15.5
Conclusion: Vangl1 and Vangl2 transcripts downregulation might be implicated in the occurrence of mouse NTDs induced by retinoic acid.
Background: Neural tube defects (NTDs) are complex disease caused by multiple genes and environmental factors. Folic acid is a known environmental factor for NTDs. Folate metabolism pathway genes have been examined for association with NTDs, but most of these genes were studied individually, often with different populations providing conflicting results.
Objective: Folate pathway genes SNPs in Chinese families with NTDs were investigated to discover the genetic and environmental factors that contribute to the cause of NTDs.
Materials and Methods: We genotyped 28 SNPs in 12 genes in a total of 117 NTDs individuals from 115 family and 216 parental controls mainly Han Chinese from central China. Family-based association analysis was performed by case-parent control study and transmission/ disequilibrium test (TDT) to evaluate the association between SNPs and environmental risk factors: no peri-pregnant folate supplementation, gestational diabetes mellitus (GDM) and peri-pregnant taking medicine. These genes are: folate receptor 1 (FOLR1), folate receptor 2 (FOLR2), solute carrier family 19 member 1 (SLC19A1), transcobalamin II (TCN2), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), betaine-homocysteine methyltransferase (BHMT), cystathionine-beta-synthase (CBS) and endothelial nitric oxide synthase 3 (NOS3).
Results: MTHFR rs1801133 was significantly associated with NTDs, and environmental risk factors, no peri-pregnant folate supplementation and GDM, had potentiation on its contribution to NTDs. BHMT rs3733890 and no peri-pregnant folate supplementation conjointly led to NTDs, while genotype can not solely cause NTDs. Other SNPs in folate pathway genes had no significant association with NTDs.
Conclusion: MTHFR rs1801133 is an independent genetic risk factor of NTDs, but BHMT rs3733890 is not a major risk factor.
Background: Region of interest (ROI) segmentation and boundaries identification are still extremely challenging task for automatic bone age assessment (ABAA).
Objective: New algorithms, particle swarm optimization (PSO) and artificial neural network (ANN) are proposed to improve the validity, accuracy and practicality of ABAA.
Materials and Methods: The concept of object-based ROI was proposed. Thirteen RUS (including radius,ulna and short finger bones) ROIs and seven carpal ROIs were appointed respectively according to Tanner-Whitehouse (TW3) method. Five features including size, morphologic features and fusion stage of each ROI were extracted and input into ANN classifiers. ANNs were built upon feed-forward multilayer networks and trained with back-propagation algorithm rules to process RUS and Carpal features respectively. About 1,046 digital left hand-wrist radiographs were randomly utilized half for training ANNs and the rest for ABAA after manual reading by revised Greulich-Pyle method.
Results: The 95% confidence intervals of the difference between ABAA and manual readings were -0.010 to 0.084 years for RUS bone age and -0.055 to 0.015 years for Carpal bone age. Both RUS and Carpal ABAA systems had no significant difference compared with manual method (t = 1.563 and -1.123, both P > 0.05), and both two systems had fairly high concordance rates (97.9% and 96.5% respectively) and similar coefficient variations (3.4 and 3.7 respectively).
Conclusion: PSO method made image segmentation and feature extraction more valid and accurate, and the ANN models were sophisticated in processing image information. ABAA system based on intelligent algorithms had been successfully applied to all cases from 0 to 18 years of bone age.
目的:研究维甲酸对胎鼠Vangl1及Vangl2基因表达的时空特征的影响。
方法:全反式维甲酸橄榄油混悬液按120 mg/kg在BALB/C小鼠怀孕第9.5天(E9.5)(G1组)或E10.5(G2组)灌胃。两组的对照组(G1c、G2c)在相同时期仅用等量纯橄榄油灌胃。分别取E10.5、E11.5、E13.5、E15.5、E17.5、E19.5胎鼠,Vangl1及Vangl2基因表达量采用逆转录酶PCR(RT-PCR)检测,其时空表达采用全胚胎原位杂交(whole-mount in situ hybridization, WISH)检测。
结果:活产NTDs的发生率及颅面部NTDs发生率G1组(100%、25.6%)均高于G2组(78.2%、5.7%),P均< 0.05。正常情况下Vangl1及Vangl2基因在整个神经胚形成过程中都有强表达。而G1组同期对照组比较,从胎鼠的脑到后神经孔Vangl1及Vangl2基因表达显著下调(P均< 0.05)。G2组则不同,二基因表达在全胚胎(从E11.5到E13.5)及神经管脊柱区(从E15.5到E19.5)显著下调并维持低表达水平,但在神经管的颅区(E15.5到E19.5)仅中度下调(P均< 0.05)。
结论:结果提示,维甲酸诱导的神经管畸形的发生可能与Vangl1及Vangl2基因转录子下调有关。
背景:神经管缺陷(neural tube defects, NTDs)是由环境危险因素与遗传危险因素间复杂的相互作用引起的。其潜在的发病机理仍然不清楚。从遗传和环境角度看,叶酸代谢相关基因都是NTDs的令人关注的候选基因。目前叶酸代谢相关基因间以及基因与环境间交互作用的研究较少,已有的文献间还存在相互矛盾。
目的:通过对叶酸代谢相关基因的单核苷酸多态性(single nucleotide polymorphism, SNPs)与多重环境危险因子交互作用的关联分析,寻找NTDs致病基因及环境危险因素。
方法:收集NTDs流产胎儿组织标本或者患者血标本(共117例)以及其双亲的血标本(共216例),记录围孕期补充叶酸、妊娠糖尿病、孕期服药史等情况。采用CEQ 8800系统进行多重SNP分析,对所有样本叶酸代谢相关的12个基因共28个SNPs测序。这些基因是:叶酸受体1及2、溶质载体家族19成员1、运钴胺蛋白II、亚甲四氢叶酸脱氢酶1、丝氨酸羟甲基转移酶1、5,10-亚甲基四氢叶酸还原酶、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶、5-甲基四氢叶酸-同型半胱氨酸甲基转移酶还原酶、甜菜碱同型半胱氨酸甲基转移酶、胱硫醚β合酶和内皮一氧化氮合酶3。
通过病例-双亲对照研究(case-parent control study)及传递/不平衡检验(transmission/ disequilibrium tests, TDT),分析SNPs与环境危险因子(孕期补充叶酸、妊娠糖尿病和孕期服药史)交互作用对NTDs发病的影响。
结果:亚甲基四氢叶酸还原酶(MTHFR)rs1801133与NTDs的关联具有显著性意义(P < 0.05),而且环境风险因子(未补充叶酸、妊娠糖尿病)对NTDs的发生起增效作用;而甜菜碱同型半胱氨酸甲基转移酶(BHMT)rs3733890仅在未补充叶酸层与NTDs存在连锁不平衡(P < 0.05),基因型本身并不能单独导致疾病;而其他基因的SNPs与NTDs的发生没有显著性关联(P均> 0.05)。
结论: MTHFR rs1801133是NTDs的危险因子,而BHMT rs3733890不是NTDs独立的危险因子。未来尚需要对更大的样本进行基因与基因、基因与环境交互作用的研究。
背景:骨龄评估对内分泌障碍与生长落后等疾病的诊断与治疗、预测成人身高等有重要指导意义。常用的骨龄评估方法中,Greulich-Pyle法具有主观性,而Tanner-Whitehouse(TW3)法操作起来较为复杂。十多年来人们一直在探索自动化骨龄评估(automatic bone age assessment, ABAA),但兴趣区(regions of interest, ROI)分割与边界的识别仍然是目前限制ABAA的富有挑战性的难题。
目的:应用两种新的算法即粒子群优化(PSO)及人工神经网络(ANN)以提高自动化骨龄评估的准确性和实用性。
方法:建立基于目标的ROI。按照Tanner-Whitehouse (TW3)法将ROI分为RUS(包括尺桡骨及掌指骨)ROI及腕骨ROI。每个兴趣区提取5项特征(包括大小、形态及融合状态)输入人工神经网络(artificial neural networks, ANN)分类器,ANN建立在前馈的多层网络基础上,并以反向传播算法规则训练ANN以分别处理RUS及腕骨特征。约1,046份左手及腕的数字X光片被随机分成两部分,一半用以训练ANN,另一半用以ABAA,而之前全部采用修订的Greulich-Pyle法人工判读骨龄。
结果:人工阅读骨龄与ABAA比较,RUS骨龄95%的可信区间是-0.010岁–0.084岁,腕骨骨龄95%的可信区间是-0.055岁–0.015岁。RUS及腕骨自动化骨龄评估结果与Greulich-Pyle法比较均具有很高的一致率(分别为97.9%与96.5%),变异系数相似(3.4与3.7),并且与人工阅读相比均无显著性差异(t=1.563与-1.123,P均> 0.05)。
结论:PSO对图像分割与特征的提取更为有效和准确。该ANN经训练后能更全面地处理影像特征信息,准确判断骨龄。基于智能算法的ABAA系统成功地应用于骨龄0–18岁所有病例。
Objective: This study reported the effects of retinoic acid upon the spatiotemporal expressions of Vangl1 and Vangl2 in mouse fetuses.
Material and method: Single dose of 120 mg/kg body weight of all trans-retinoic acid suspended in olive oil was administered intragastrically to each pregnant BALB/C mice on embryonic day (E) 9.5 (group 1, G1) or E10.5 (group 2, G2); mice treated with pure olive oil on E9.5 or E10.5 served as control groups. The expressions of Vangl1 and Vangl2 in fetuses were investigated by reverse transcriptase PCR (RT-PCR) and their spatial and temporal expressions were detected by whole-mount in situ hybridization (WISH) on E10.5, E11.5, E13.5, E15.5, E17.5 and E19.5 respectively.
Results: The study indicated that the incidence of NTDs in live birth and craniofacial NTDs rate were significantly higher in G1 (100% and 25.6%) than that in G2 (78.2% and 5.7%), both P < 0.05. Vangl1 and Vangl2 were strongly expressed throughout neurulation in embryos of control groups. G1 embryos exhibited a dramatic downregulation of Vangl1 and Vangl2 expressions from cranial region to posterior neuropore compared with the control group of G1 (all P < 0.05). In contrast, the both transcripts in G2 embryos were significantly downregulated and weakly expressed in whole embryos from E11.5 to E13.5 and in the spinal region of neural tube from E15.5 to E19.5, but moderately downregulated in the cranial region of neural tube from E15.5
Conclusion: Vangl1 and Vangl2 transcripts downregulation might be implicated in the occurrence of mouse NTDs induced by retinoic acid.
Background: Neural tube defects (NTDs) are complex disease caused by multiple genes and environmental factors. Folic acid is a known environmental factor for NTDs. Folate metabolism pathway genes have been examined for association with NTDs, but most of these genes were studied individually, often with different populations providing conflicting results.
Objective: Folate pathway genes SNPs in Chinese families with NTDs were investigated to discover the genetic and environmental factors that contribute to the cause of NTDs.
Materials and Methods: We genotyped 28 SNPs in 12 genes in a total of 117 NTDs individuals from 115 family and 216 parental controls mainly Han Chinese from central China. Family-based association analysis was performed by case-parent control study and transmission/ disequilibrium test (TDT) to evaluate the association between SNPs and environmental risk factors: no peri-pregnant folate supplementation, gestational diabetes mellitus (GDM) and peri-pregnant taking medicine. These genes are: folate receptor 1 (FOLR1), folate receptor 2 (FOLR2), solute carrier family 19 member 1 (SLC19A1), transcobalamin II (TCN2), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR), betaine-homocysteine methyltransferase (BHMT), cystathionine-beta-synthase (CBS) and endothelial nitric oxide synthase 3 (NOS3).
Results: MTHFR rs1801133 was significantly associated with NTDs, and environmental risk factors, no peri-pregnant folate supplementation and GDM, had potentiation on its contribution to NTDs. BHMT rs3733890 and no peri-pregnant folate supplementation conjointly led to NTDs, while genotype can not solely cause NTDs. Other SNPs in folate pathway genes had no significant association with NTDs.
Conclusion: MTHFR rs1801133 is an independent genetic risk factor of NTDs, but BHMT rs3733890 is not a major risk factor.
Background: Region of interest (ROI) segmentation and boundaries identification are still extremely challenging task for automatic bone age assessment (ABAA).
Objective: New algorithms, particle swarm optimization (PSO) and artificial neural network (ANN) are proposed to improve the validity, accuracy and practicality of ABAA.
Materials and Methods: The concept of object-based ROI was proposed. Thirteen RUS (including radius,ulna and short finger bones) ROIs and seven carpal ROIs were appointed respectively according to Tanner-Whitehouse (TW3) method. Five features including size, morphologic features and fusion stage of each ROI were extracted and input into ANN classifiers. ANNs were built upon feed-forward multilayer networks and trained with back-propagation algorithm rules to process RUS and Carpal features respectively. About 1,046 digital left hand-wrist radiographs were randomly utilized half for training ANNs and the rest for ABAA after manual reading by revised Greulich-Pyle method.
Results: The 95% confidence intervals of the difference between ABAA and manual readings were -0.010 to 0.084 years for RUS bone age and -0.055 to 0.015 years for Carpal bone age. Both RUS and Carpal ABAA systems had no significant difference compared with manual method (t = 1.563 and -1.123, both P > 0.05), and both two systems had fairly high concordance rates (97.9% and 96.5% respectively) and similar coefficient variations (3.4 and 3.7 respectively).
Conclusion: PSO method made image segmentation and feature extraction more valid and accurate, and the ANN models were sophisticated in processing image information. ABAA system based on intelligent algorithms had been successfully applied to all cases from 0 to 18 years of bone age.
引文
1. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, Speer MC. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol 2005; 27(3):515–524.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol 2006; 76(4):237–240.
3. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262(20):2847–2852.
4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338 (8760):131–137.
5. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 1992; 41(RR-14):1–7.
6. Doudney K, Ybot-Gonzalez P, Paternotte C, Stevenson RE, Greene ND, Moore GE, et al. Analysis of the planar cell polarity gene Vangl2 and its co-expressed paralogue Vangl1 in neural tube defect patients. Am J Med Genet A 2005; 136(1):90–92.
7. Katoh Y, Katoh M. Comparative genomics on Vangl1 and Vangl2 genes. Int J Oncol 2005; 26(5):1435–1440.
8. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet 2003; 4(10):784–793.
9. Kibar Z, Vogan KJ, Groulx N, Justice MJ, Underhill DA, Gros P. Ltap, amammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nat Genet 2001; 28(3):251–255.
10. Murdoch JN, Doudney K, Paternotte C, Copp AJ, Stanier P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum Mol Genet 2001; 10(22):2593–2601.
11. Fantel AG, Shepard TH, Newell-Morris LL, Moffett BC. Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina). I. General features. Teratology 1977; 15(1): 65–71.
12. Kalter H. The teratogenic effects of hypervitaminosis A upon the face and mouth of inbred mice. Ann NY Acad Sci 1960; 85: 42–55.
13. Kistler A. Teratogenesis of retinoic acid in rats: susceptible stages and suppression of retinoic acid-induced limb malformations by cycloheximide. Teratology 1981; 23(1): 25–31.
14. Soprano DR, Soprano KJ. Retinoids as teratogens. Annu Rev Nutr 1995; 15:111–132.
15. Harland RM. In situ hybridization: an improved whole-mount method for Xenopus embryos. Methods Cell Biol 1991; 36:685–695.
16. Wessely O, Tran U, Zakin L, De Robertis EM. Identification and expression of the mammalian homologue of Bicaudal-C. Mech Dev 2001; 101(1–2):267–270.
17. Agnish ND, Kochhar DM. Developmental toxicology of retinoids. In: Retinoids in Clinical Practice, edited by G. Koren. New York, NY: Dekker, 1992. 47–76.
18. Seegmiller RE, Ford WH, Carter MW, Mitala JJ, Powers WJ Jr. A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats. J Am Acad Dermatol 1997; 36(3 Pt 2): S60–66.
19. Zhang Y, Liu K, Gao Y, Li S. Modulation of Dishevelled and Vangl2 by all-trans-retinoic acid in the developing mouse central nervous system and its relationship to teratogenesis. Acta Biochim Biophys Sin (Shanghai) 2007; 39(9):684–692.
20. Dencker L, D’Argy R, Danielsson BR, Ghantous H, and Sperber GO. Saturable accumulation of retinoic acid in neural and neural crest derived cells in early embryonic development. Dev Pharmacol Ther 1987; 10(3): 212–223.
21. Harnish DC, Jiang H, Soprano KJ, Kochhar DM, Soprano DR. Retinoic acid receptor beta 2 mRNA is elevated by retinoic acid in vivo in susceptible regions of mid-gestation mouse embryos. Dev Dyn 1992; 194(3): 239–246.
22. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell 1993; 73(4): 643–658.
23. Iulianella A, Lohnes D. Contribution of retinoic acid receptor gamma to retinoid-induced craniofacial and axial defects. Dev Dyn 1997; 209(1):92–104.
24. Torban E, Wang HJ, Groulx N, Gros P. Independent mutations in mouse Vangl2 that cause neural tube defects in loop-tail mice impair interaction with members of the Dishevelled family. J Biol Chem 2004; 279(50):52703–52713.
25. Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, et al. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med 2007; 356(14):1432–1437.
26. Jessen JR, Solnica-Krezel L. Identification and developmental expression pattern of van gogh-like 1, a second zebrafish strabismus homologue. Gene Expr Patterns 2004; 4(3):339–344.
1. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, et al. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol, 2005, 27(3):515–524.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol, 2006, 76(4):237–240.
3. Elwood JM, Little J, Elwood JH. Epidemiology and Control of Neural Tube Defects. Oxford, UK: Oxford University Press. 1992.
4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 1991, 338(8760):131–137.
5. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(pt 5):379–396.
6. Razin A, Kantor B. DNA methylation in epigenetic control of gene expression. Prog Mol Subcell Biol, 2005, 38:151–167. Review.
7. Rosenquist TH, Finnell RH. Genes, folate and homocysteine in embryonic development. Proc Nutr Soc, 2001, 60(1):53–61. Review.
8. Shields DC, Kirke PN, Mills JL, Ramsbottom D, Molloy AM, Burke H, et al. The“thermolabile”variant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of the genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet, 1999, 64(4):1045–1055.
9. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet, 1995, 346(8982):1070–1071.
10. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet, 2002, 47(6):319–324.
11. Gonzalez-Herrera L, Garcia-Escalante G, Castillo-Zapata I, Canto-Herrera J, Ceballos-Quintal J, Pinto-Escalante D, et al. Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico. Clin Genet, 2002, 62(5):394–398.
12. Gutiérrez Revilla JI, Pérez Hernández F, Calvo Martín MT, Tamparillas Salvador M, Gracia Romero J. C677T and A1298C MTHFR polymorphisms in the etiologyof neural tube defects in Spanish population. Med Clin (Barc), 2003, 120(12):441–445.
13. Takimoto H, Mito N, Umegaki K, Ishiwaki A, Kusama K, Abe S, et al. Relationship between dietary folate intakes, maternal plasma total homocysteine and B-vitamins during pregnancy and fetal growth in Japan. Eur J Nutr, 2007, 46(5):300–306.
14. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet, 1995, 345(8943):149–151.
15. Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, et al. Analysis of select folate pathway genes, PAX3, and human T in a midwestern neural tube defect population. Teratology, 1999, 59(5):331–341.
16. Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, et al. Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet A, 2003, 119(2):172–176.
17. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(pt 5):379–396.
18. Brown KS, Cook M, Hoess K, Whitehead AS, Mitchell LE. Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus. Birth Defects Res A Clin Mol Teratol. 2004. 70(3):101–106.
19. Sun F, Flanders WD, Yang Q, Khoury MJ. A new method for estimating the risk ratio in studies using case-parental control design. Am J Epidemiol, 1998, 148(9):902–909.
20. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet, 1993, 52(3):506–516.
21. Posey DL, Khoury MJ, Mulinare J, Adams MJ Jr, Ou CY. Is mutated MTHFR a risk factor for neural tube defects? Lancet, 1996, 347(9002):686–687.
22. van der Put NM, van den Heuvel LP, Steegers-Theunissen RP, Trijbels FJ, Eskes TK, Mariman EC, et al. Decreased methylene tetrahydrofolate reductase activity due to the 677C→T mutation in families with spina bifida offspring. J Mol Med, 1996, 74(11):691–694. Erratum in: J Mol Med, 1997, 75(1):69.
23. van der Put NM, Thomas CM, Eskes TK, Trijbels FJ, Steegers-Theunissen RP, Mariman EC, et al. Altered folate and vitamin B-12 metabolism in families with spina bifida offspring. QJM, 1997, 90(8):505–510.
24. Kang SS. Treatment of hyperhomocyst(e)inemia: physiological basis. J Nutr, 1996, 126(4 Suppl):1273S–1275S.
25. Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, Suh DS, et al. Investigations of a common genetic methyltransferase (BHMT) variant in betaine-homocysteine in coronary artery disease. Atherosclerosis, 2003, 167(2):205–214.
26. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol, 2000, 151(9):862–877.
27. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet, 1995, 10(1):111–113.
28. Alozie Arole CN, Puder KS, Reznar M, Eby E, Zhu BP. Folic acid awareness in Michigan, 1996–1999. Obstet Gynecol, 2003, 102(5 Pt 1):1046–1050.
29. Rampersaud E, Melvin EC, Siegel D, Mehltretter L, Dickerson ME, George TM, et al. Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects. Clin Genet, 2003, 63(3):210–214.
30. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC; NTD Collaborative Group. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect, 2006, 114(10):1547–1552.
1. Greulich WW, Pyle SI, ed. Radiographic atlas of skeletal development of hand wrist. Second ed. Stanford, CA: Stanford University Press, 1971.
2. Tanner JM, Healy MJR, Goldstein H, Cameron N, ed. Assessment of skeletal maturity and prediction of adult height (TW3 method). 3rd ed. London: WB Saunders, 2001, 1–108.
3. Zhang A, Gertych A, Liu BJ. Automatic bone age assessment for young children from newborn to 7-year-old using carpal bones. Comput Med Imaging Graph 2007, 31(4-5):299–310.
4. Pietka E, Pospiech S, Gertych A, Cao F. Integration of computer assisted bone age assessment with clinical PACS. Comput Med Imag Grap 2002, 1–12.
5. Zhang A, Cao F, Pietka E, Liu BJ, Huang HK. Data mining for average images in a digital hand atlas. Proc SPIE Med Imag 2004, 5371:251–258.
6. Kennedy J, Eberhart RC. Particle swarm optimization. Proceedings of IEEE international conference on neural networks. Piscataway, NJ. 1995:1942–1948.
7. Eberhart RC, Kennedy J. A new optimizer using particle swarm theory. Proceedings of the sixth international symposium on micromachine and human science. Nagoya, Japan, 1995:39–43.
8. Meissner M, Schmuker M, Schneider G. Optimized Particle Swarm Optimization(OPSO) and its application to artificial neural network training. BMC Bioinformatics 2006, 7:125.
9. Liu Z, Liu J, Chen JX. Automatic bone age assessment based on PSO. Proceedings of the 1st International conference on bioinformatics and biomedical engineering. Wuhan, China. 2007: 453–455.
10. Bull RK, Edwards PD, Kemp PM, Fry S, Hughes IA. Bone age assessment: a large scale comparison of the Greulich and Pyle, and Tanner and Whitehouse (TW2) methods. Arch Dis Child 1999, 81(2):172–173.
11. Hsieh CW, Jong TL, Tiu CM. Bone age estimation based on phalanx information with fuzzy constrain of carpals. Med Biol Eng Comput 2007, 45(3):283–295.
12. Pietka E, Gertych A, Pospiech S, Cao F, Huang HK, Gilsanz V. Computer-assisted bone age assessment: image preprocessing and epiphyseal/metaphyseal ROI extraction. IEEE Trans Med Imaging 2001, 20(8):715–729.
13. Pietka BE, Po?piech S, Gertych A, Cao F, Huang HK, Gilsanz V. Computer automated approach to the extraction of epiphyseal regions in hand radiographs. J Digit Imaging 2001, 14(4):165–172.
14. Koc A, Karaoglanoglu M, Erdogan M, Kosecik M, Cesur Y. Assessment of bone ages: is the Greulich-Pyle method sufficient for Turkish boys? Pediatr Int 2001, 43(6):662–665.
15. Schmeling A, Schulz R, Danner B, R?sing FW. The impact of economic progress and modernization in medicine on the ossification of hand and wrist. Int J Legal Med 2006, 120(2):121–126.
1. Harris MJ, Juriloff DM. Mini-review: Toward understanding mechanisms of genetic neural tube defects in mice. Teratol, 1999, 60(5):292–305.
2. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA, 1991, 262(20): 2847–2852.
3. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet, 1991, 338(8760):131–137.
4. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep, 1992, 41(RR-14):1-7. Review.
5. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol, 2000, 151(9):862–877.
6. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(Pt. 5):379–396.
7. Chatkupt S, Skurnick JH, Jaggi M, Mitruka K, Koenigsberger MR, Johnson WG. Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s. Neurol, 1994, 44(1):65–70.
8. Guney O, Canbilen A, Konak A, Acar O. The effects of folic acid in the prevention of neural tube development defects caused by phenytoin in early chick embryos. Spine, 2003, 28(5):442–445.
9. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet, 1995, 346(8982):1070–1071.
10. Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, et al. Analysis of select folate pathway genes, PAX3, and human T in a Midwesternneural tube defect population. Teratology, 1999, 59(5):331-41.
11. Elwood JM, Little J, Elwood JH. Epidemiology and control of neural tube defects. Oxford: Oxford University Press. 1992.
12. Ross SA, McCaffery PJ, Drager UC, De Luca LM. Retinoids in embryonal development. Physiol Rev, 2000, 80(3):1021–1054.
13. National Research Council. Scientific frontiers in developmental toxicology and risk assessment. Washington, D.C.: National Academy Press. 2000.
14. Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, et al. Testing for genetic associations in a spina bifida population: Analysis of the HOX gene family and human candidate gene regions implicated by mouse models of neural tube defects. Am J Med Genet, 2002, 110(3):203–207.
15. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet, 1995, 10(1):111–113.
16. Shields DC, Kirke PN, Mills JL, Ramsbottom D, Molloy AM, Burke H, et al. The‘‘thermolabile’’variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of the genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet, 1999, 64(4):1045–1055.
17. Alozie Arole CN, Puder KS, Reznar M, Eby E, Zhu BP. Folic acid awareness in Michigan, 1996–1999. Obstet Gynecol, 2003, 102(5 Pt 1):1046–1050.
18. Rampersaud E, Melvin EC, Siegel D, Mehltretter L, Dickerson ME, George TM, et al. Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects. Clin Genet, 2003, 63(3):210–214.
19. Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, et al. 2003. Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet A, 2003, 119(2): 172–176.
20. Felder B, Stegmann K, Schultealbert A, Geller F, Strehl E, Ermert A, et al.Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs). Eur J Hum Genet, 2002, 10(11):753–756.
21. Ramsbottom D, Scott JM, Molloy A, Weir DG, Kirke PN, Mills JL, et al. Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects? Clin Genet, 1997, 51(1):39–42.
22. Zhao R, Zhu H, Dao J, Li Z. Study on genotypes of cystathionine beta-synthase in neural tube defects. Wei Sheng Yan Jiu, 2000, 29(1):50–51.
23. Dickerson M, Joseph J, George M, Enterline DS, Melvin EC, Gilbert JR, Linney E, Speer MC, NTD Collaborative Group. CYP26A1 and RALDH2 are not implicated in the development of human neural tube defects. Am J Hum Gen, 2002, 71:469.
24. Klootwijk R, Hol FA, Wu M, Willemen JJ, Groenen P, Hamel B, et al. Genetic variation analysis of MLP, TFAP2A, and CSK in patients with neural tube defects. J Med Genet, 2003, 40(4):e43.
25. Speer MC, Rampersaud E, Melvin EC, George TM, Allen J, Floyd LE, Dickerson M, NTD Collaborative Group. Genomic screening and testing of candidate genes in human neural tube defects. International Neural Tube Defects Conference. 2003.
26. Vieira AR, Trembath D, Vandyke DC, Murray JC, Marker S, Lerner G, et al. Studies with His475Tyr glutamate carboxypeptidase II polymorphism and neural tube defects. Am J Med Genet, 2002, 111(1): 218–219.
27. Afman LA, Trijbels FJ, Blom HJ. The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans. J Nutr, 2003, 133(1):75–77.
28. Stumpo DJ, Eddy RL, Haley LL, Sait S, Shows TB, Lai WS, et al. Promoter sequence, expression, and fine chromosomal mapping of the human gene (MLP)encoding the MARCKS-like protein: Identification of neighboring and linked polymorphic loci for MLP and MACS and use in the evaluation of human neural tube defects. Genomics, 1998, 49(2):253–264.
29. Stegmann K, Boecker J, Richter B, Capra V, Finnell RH, Ngo ET, et al. A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects. Teratology, 2001, 63(5):167–175.
30. Hol FA, Geurds MP, Chatkupt S, Shugart YY, Balling R, Schrander-Stumpel CT, et al. PAX genes and human neural tube defects: An amino acid substitution in PAX1 in a patient with spina bifida. J Med Genet, 1996, 33(8):655–660.
31. Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet, 2002, 71(5):1207–1215.
32. Stegmann K, Ziegler A, Ngo ET, Kohlschmidt N, Schr?ter B, Ermert A, et al. Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects (NTD). Am J Med Genet, 1999, 87(1):23–29.
33. Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet, 1999, 84(2):151–157.
34. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet, 2002, 47(6):319–324.
35. Johanning GL, Wenstrom KD, Tamura T. Changes in frequencies of heterozygous thermolabile 5,10-methylenetetrahydrofolate reductase gene in fetuses with neural tube defects. J Med Genet, 2002, 39(5):366–367.
36. Cunha AL, Hirata MH, Kim CA, Guerra-Shinohara EM, Nonoyama K, Hirata RD. Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects. Clin Chim Acta, 2002, 318(1-2):139–143.
37. Gonzalez-Herrera L, Garcia-Escalante G, Castillo-Zapata I, Canto-Herrera J, Ceballos-Quintal J, Pinto-Escalante D, et al. Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico. Clin Genet, 2002, 62(5): 394–398.
38. Pietrzyk JJ, Bik-Multanowski M, Sanak M, Twardowska M. Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. J Appl Genet, 2003, 44(1):111–113.
39. Gutiérrez Revilla JI, Pérez Hernández F, Calvo Martín MT, Tamparillas Salvador M, Gracia Romero J. C677T and A1298C MTHFR polymorphisms in the etiology of neural tube defects in Spanish population. Med Clin (Barc), 2003, 120(12):441–445.
40. Brody LC, Baker PJ, Chines PS, Musick A, Molloy AM, Swanson DA, et al. Methionine synthase: high-resolution mapping of the human gene and evaluationas a candidate locus for neural tube defects. Mol Genet Metab, 1999, 67(4):324–333.
41. Guéant-Rodriguez RM, Rendeli C, Namour B, Venuti L, Romano A, Anello G, et al. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans. Neurosci Lett, 2003, 344(3):189–192.
42. Wilson A, Platt R,Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab, 1999, 67(4):317–323.
43. Rogner UC, Danoy P, Matsuda F, Moore GE, Stanier P, Avner P. SNPs in the CpG island of NAP1L2: A possible link between DNA methylation and neural tube defects? Am J Med Genet, 2002, 110(3):208–214.
44. Deak KL, Boyles AL, Etchevers HC, Melvin EC, Siegel DG, Graham FL, et al. SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Hum Genet, 2005, 117(2-3):133-142.
45. Bauer KA, George TM, Enterline DS, Stottmann RW, Melvin EC, Siegel D, Samal S, Hauser MA, Klingensmith J, Nye JS, Speer MC, Neural Tube Defects Collaborative Group. A novel mutation in the gene encoding noggin is not causative in human neural tube defects. Neurogenet, 2002, 16(1):65–71.
46. Chatkupt S, Hol FA, Shugart YY, Geurds MP, Stenroos ES, Koenigsberger MR, et al. Absence of linkage between familial neural tube defects and PAX3 gene. J Med Genet, 1995, 32(3):200–204.
47. Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, et al. Testing for genetic associations with the PAX gene family in a spina bifida population. Am J Med Genet, 202, 110(3):195–202.
48. Joosten PH, Toepoel M, Mariman EC, Van Zoelen EJ. Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects. Nat Genet, 2001, 27(2):215–217.
49. Joosten PH, Toepoel M, van Oosterhout D, Afink GB, van Zoelen EJ. A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors. Biochim Biophys Acta, 2002, 1588(3):254–260.
50. De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH, et al. Reduced folate carrier polymorphism (80A→G) and neural tube defects. Eur J Hum Genet, 2003, 11(3):245–252.
51. Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet, 2002, 108(1):1–6.
52. Vargas FR, Roessler E, Gaudenz K, Belloni E, Whitehead AS, Kirke PN, et al. Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly. Hum Genet, 1998, 102(4):387–392.
53. Kirillova I, Novikova I, AugéJ, Audollent S, Esnault D, Encha-Razavi F, et al. Expression of the sonic hedgehog gene in human embryos with neural tube defects. Teratology, 2000, 61(5):347–354.
54. Zhu H, Barber R, Shaw GM, Lammer EJ, Finnell RH. Is sonic hedgehog (SHH) a candidate gene for spina bifida? A pilot study. Am J Med Genet A, 2003, 117(1):87–88.
55. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab, 2001, 73(2):164–172.
56. Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, Molloy AM, et al. Association between historically high frequencies of neural tube defects and the human T homologue of moute T (Brachyrury). Am J Med Genet, 2000, 92(3):206–211.
57. Richter B, Schultealbert AH, Koch MC. Human T and risk for neural tube defects. J Med Genet, 2000, 39(3):E14.
58. Afman LA, Lievers KJ, van der Put NM, Trijbels FJ, Blom HJ. Single nucleotide polymorphisms in the transcobalamin gene: Relationship with transcobalamin concentrations and risk for neural tube defects. Eur J Hum Genet, 2002, 10(7):433–438.
59. Benz LP, Swift FE, Graham FL, Enterline DS, Melvin EC, Hammock P, Gilbert JR, Speer MC, Bassuk AG, Kessler JA, George TM, and the NTD Collaborative Group. TERC is not a major gene in human neural tube defects. Birth Defects Res A: Clin Molec Teratol, 2004, 70(8):531–533.
60. Volcik KA, Shaw GM, Zhu H, Lammer EJ, Finnell RH. Risk factors for neural tube defects: Associations between uncoupling protein 2 polymorphisms and spina bifida. Birth Defects Res A Clin Molec Teratol, 2003, 67(3):158–161.
61. Newton R, Stanier P, Loughna S, Henderson DJ, Forbes SA, Farrall M, et al. Linkage analysis of 62 X-chromosomal loci excludes the X chromosome in an Icelandic family showing apparent X-linked recessive inheritance of neural tube defects. Clin Genet, 1994, 45(5):241–249.
62. Brown LY, Hodge SE, Johnson WG, Guy SG, Nye JS, Brown S. Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene. Am J Med Genet, 2002, 108(2):128–131.
63. Zhu H, Junker WM, Finnell RH, Brown S, Shaw GM, Lammer EJ, et al. Lack of association between ZIC2 and ZIC3 genes and the risk of neural tube defects (NTDs) in Hispanic populations. Am J Med Genet A, 2003, 116(4):414–415.
64. Carrel T, Herman GE, Moore GE, Stanier P. Lack of mutations in ZIC3 in three families with neural tube defects. Am J Med Genet, 2001, 98(3):283–285.
1. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003, 4(10):784–93.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol, 2006, 76(4):237–240.
3. Lalouel JM, Morton NE, Jackson J. Neural tube malformations: complex segregation analysis and calculation of recurrence risks. J Med Genet, 1979, 16(1):8–13.
4. Van Allen MI, Kalousek DK, Chernoff GF, Juriloff D, Harris M, McGillivray BC, et al. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet, 1993, 47(5):723–743. Review.
5. Strong LC, Hollander WF. Hereditary loop-tail in the house mouse. J Hered, 1949, 40:329–334.
6. Rachel RA, Murdoch JN, Beermann F, Copp AJ, Mason CA. Retinal axonmisrouting at the optic chiasm in mice with neural tube closure defects. Genesis, 2000, 27(1):32–47.
7. Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B, Copp AJ, et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr Biol, 2003, 13(13):1129–1133.
8. Lu X, Borchers AG, Jolicoeur C, Rayburn H, Baker JC, Tessier-Lavigne M. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature, 2004, 430(6995):93–98.
9. Hamblet NS, Lijam N, Ruiz-Lozano P, Wang J, Yang Y, Luo Z, et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development, 2002, 129(24):5827–5838.
10. Murdoch JN, Rachel RA, Shah S, Beermann F, Stanier P, Mason CA, et al. Circletail, a new mouse mutant with severe neural tube defects: chromosomal localization and interaction with the loop-tail mutation. Genomics, 2001, 78(1–2):55–63.
11. Wallingford JB, Harland RM. Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. Development, 2001, 128(13):2581–2592.
12. Strutt DI. The asymmetric subcellular localization of components of the planar polarity pathway. Semin Cell Dev Biol, 2002, 13(3):225–231.
13. Tree DR, Ma D, Axelrod JD. A three-tiered mechanism for regulation of planar cell polarity. Semin Cell Dev Biol, 2002, 13(3):217–224.
14. Mlodzik M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet, 2002, 18(11):564–571.Review.
15. Das G, Jenny A, Klein TJ, Eaton S, Mlodzik M. Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development, 2004, 131(18):4467–4476.
16. Jenny A, Reynolds-Kenneally J, Das G, Burnett M, Mlodzik M. Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding. Nat Cell Biol, 2005, 7(7):691–697.
17. Wang J, Hamblet NS, Mark S, Dickinson ME, Brinkman BC, Segil N, et al. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development, 2006, 133(9):1767–1778.
18. Hamblet NS, Lijam N, Ruiz-Lozano P, Wang J, Yang Y, Luo Z, et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development, 2002, 129(24):5827–5838.
19. Wallingford JB, Harland RM. Neural tube closure requires Dishevelled-dependent convergent extension of the midline. Development, 2002, 129(24):5815–5825.
20. Heisenberg CP, Tada M, Rauch GJ, Saúde L, Concha ML, Geisler R, et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature, 2000, 405(6782):76–81.
21. Tissir F, De-Backer O, Goffinet AM, Lambert de Rouvroit C. Developmental expression profiles of Celsr (Flamingo) genes in the mouse. Mech Dev, 2002, 112(1–2):157–160.
22. Torban E, Kor C, Gros P. Van Gogh-like2 (Strabismus) and its role in planar cell polarity and convergent extension in vertebrates. Trends Genet, 2004, 20(11):570–577.
23. Goto T, Keller R. The planar cell polarity gene strabismus regulates convergence and extension and neural fold closure in Xenopus. Dev Biol, 2002, 247(1):165–181.
24. Bastock R, Strutt H, Strutt D. Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development, 2003, 130(13):3007–3014.
25. Jenny A, Darken RS, Wilson PA, Mlodzik M. Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling. EMBO J, 2003, 22(17):4409–4420.
26. Murdoch JN, Doudney K, Paternotte C, Copp AJ, Stanier P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum Mol Genet, 2001, 10(22):2593–2601.
27. Katoh Y, Katoh M. Comparative genomics on Vangl1 and Vangl2 genes. Int J Oncol, 2005, 26(5):1435–1440.
28. Torban E, Wang HJ, Groulx N, Gros P. Independent mutations in mouse Vangl2 that cause neural tube defects in looptail mice impair interaction with members of the Dishevelled family. J Biol Chem, 2004, 279(50):52703–52713.
29. Liu J, Qi J, Zhu J, Zhang L, Liang Y, Ning Q, Luo X. Effects of retinoic acid on the expressions of Vangl1 and Vangl2 in mouse fetuses. J Neurogenet, 2008 (In press).
30. Hotta K, Takahashi H, Asakura T, Saitoh B, Takatori N, Satou Y, et al. Characterization of Brachyury–downstream notochord genes in the Ciona intestinalis embryo. Dev Biol, 2000, 224(1):69–80.
31. Wallingford JB, Goto T, Keller R, Harland RM. Cloning and expression ofXenopus Prickle, an orthologue of a Drosophila planar cell polarity gene. Mech Dev, 2002, 116(1–2):183–186.
32. Takeuchi M, Nakabayashi J, Sakaguchi T, Yamamoto TS, Takahashi H, Takeda H, et al. The prickle–related gene in vertebrates is essential for gastrulation cell movements. Curr Biol, 2003, 13(8):674–679.
33. Veeman MT, Slusarski DC, Kaykas A, Louie SH, Moon RT. Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol, 2003, 13(8):680–685.
34. Povelones M, Nusse R. The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J, 2005, 24(19):3493–3503.
35. Carron C, Pascal A, Djiane A, Boucaut JC, Shi DL, Umbhauer M. Frizzled receptor dimerization is sufficient to activate the Wnt/beta-catenin pathway. J Cell Sci, 2003, 116(Pt 12):2541–2550.
36. Fanto M, McNeill H. Planar polarity from flies to vertebrates. J Cell Sci, 2004, 117(Pt 4):527–533.
37. Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature, 2000, 403(6770):676–680.
38. Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, et al. The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev, 2002, 16(16):2073–2084.
39. Strutt DI, Weber U, Mlodzik M. The role of RhoA in tissue polarity and Frizzled signalling. Nature, 1997, 387(6630):292–295.
40. Winter CG, Wang B, Ballew A, Royou A, Karess R, Axelrod JD, et al. DrosophilaRho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell, 2001, 105(1):81–91.
41. Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, et al. Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development, 2001, 128(15):2953–2962.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol 2006; 76(4):237–240.
3. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA 1989; 262(20):2847–2852.
4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338 (8760):131–137.
5. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep 1992; 41(RR-14):1–7.
6. Doudney K, Ybot-Gonzalez P, Paternotte C, Stevenson RE, Greene ND, Moore GE, et al. Analysis of the planar cell polarity gene Vangl2 and its co-expressed paralogue Vangl1 in neural tube defect patients. Am J Med Genet A 2005; 136(1):90–92.
7. Katoh Y, Katoh M. Comparative genomics on Vangl1 and Vangl2 genes. Int J Oncol 2005; 26(5):1435–1440.
8. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet 2003; 4(10):784–793.
9. Kibar Z, Vogan KJ, Groulx N, Justice MJ, Underhill DA, Gros P. Ltap, amammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nat Genet 2001; 28(3):251–255.
10. Murdoch JN, Doudney K, Paternotte C, Copp AJ, Stanier P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum Mol Genet 2001; 10(22):2593–2601.
11. Fantel AG, Shepard TH, Newell-Morris LL, Moffett BC. Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina). I. General features. Teratology 1977; 15(1): 65–71.
12. Kalter H. The teratogenic effects of hypervitaminosis A upon the face and mouth of inbred mice. Ann NY Acad Sci 1960; 85: 42–55.
13. Kistler A. Teratogenesis of retinoic acid in rats: susceptible stages and suppression of retinoic acid-induced limb malformations by cycloheximide. Teratology 1981; 23(1): 25–31.
14. Soprano DR, Soprano KJ. Retinoids as teratogens. Annu Rev Nutr 1995; 15:111–132.
15. Harland RM. In situ hybridization: an improved whole-mount method for Xenopus embryos. Methods Cell Biol 1991; 36:685–695.
16. Wessely O, Tran U, Zakin L, De Robertis EM. Identification and expression of the mammalian homologue of Bicaudal-C. Mech Dev 2001; 101(1–2):267–270.
17. Agnish ND, Kochhar DM. Developmental toxicology of retinoids. In: Retinoids in Clinical Practice, edited by G. Koren. New York, NY: Dekker, 1992. 47–76.
18. Seegmiller RE, Ford WH, Carter MW, Mitala JJ, Powers WJ Jr. A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats. J Am Acad Dermatol 1997; 36(3 Pt 2): S60–66.
19. Zhang Y, Liu K, Gao Y, Li S. Modulation of Dishevelled and Vangl2 by all-trans-retinoic acid in the developing mouse central nervous system and its relationship to teratogenesis. Acta Biochim Biophys Sin (Shanghai) 2007; 39(9):684–692.
20. Dencker L, D’Argy R, Danielsson BR, Ghantous H, and Sperber GO. Saturable accumulation of retinoic acid in neural and neural crest derived cells in early embryonic development. Dev Pharmacol Ther 1987; 10(3): 212–223.
21. Harnish DC, Jiang H, Soprano KJ, Kochhar DM, Soprano DR. Retinoic acid receptor beta 2 mRNA is elevated by retinoic acid in vivo in susceptible regions of mid-gestation mouse embryos. Dev Dyn 1992; 194(3): 239–246.
22. Lohnes D, Kastner P, Dierich A, Mark M, LeMeur M, Chambon P. Function of retinoic acid receptor gamma in the mouse. Cell 1993; 73(4): 643–658.
23. Iulianella A, Lohnes D. Contribution of retinoic acid receptor gamma to retinoid-induced craniofacial and axial defects. Dev Dyn 1997; 209(1):92–104.
24. Torban E, Wang HJ, Groulx N, Gros P. Independent mutations in mouse Vangl2 that cause neural tube defects in loop-tail mice impair interaction with members of the Dishevelled family. J Biol Chem 2004; 279(50):52703–52713.
25. Kibar Z, Torban E, McDearmid JR, Reynolds A, Berghout J, Mathieu M, et al. Mutations in VANGL1 associated with neural-tube defects. N Engl J Med 2007; 356(14):1432–1437.
26. Jessen JR, Solnica-Krezel L. Identification and developmental expression pattern of van gogh-like 1, a second zebrafish strabismus homologue. Gene Expr Patterns 2004; 4(3):339–344.
1. Detrait ER, George TM, Etchevers HC, Gilbert JR, Vekemans M, et al. Human neural tube defects: developmental biology, epidemiology, and genetics. Neurotoxicol Teratol, 2005, 27(3):515–524.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol, 2006, 76(4):237–240.
3. Elwood JM, Little J, Elwood JH. Epidemiology and Control of Neural Tube Defects. Oxford, UK: Oxford University Press. 1992.
4. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet, 1991, 338(8760):131–137.
5. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(pt 5):379–396.
6. Razin A, Kantor B. DNA methylation in epigenetic control of gene expression. Prog Mol Subcell Biol, 2005, 38:151–167. Review.
7. Rosenquist TH, Finnell RH. Genes, folate and homocysteine in embryonic development. Proc Nutr Soc, 2001, 60(1):53–61. Review.
8. Shields DC, Kirke PN, Mills JL, Ramsbottom D, Molloy AM, Burke H, et al. The“thermolabile”variant of methylenetetrahydrofolate reductase and neural tube defects: an evaluation of the genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet, 1999, 64(4):1045–1055.
9. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet, 1995, 346(8982):1070–1071.
10. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet, 2002, 47(6):319–324.
11. Gonzalez-Herrera L, Garcia-Escalante G, Castillo-Zapata I, Canto-Herrera J, Ceballos-Quintal J, Pinto-Escalante D, et al. Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico. Clin Genet, 2002, 62(5):394–398.
12. Gutiérrez Revilla JI, Pérez Hernández F, Calvo Martín MT, Tamparillas Salvador M, Gracia Romero J. C677T and A1298C MTHFR polymorphisms in the etiologyof neural tube defects in Spanish population. Med Clin (Barc), 2003, 120(12):441–445.
13. Takimoto H, Mito N, Umegaki K, Ishiwaki A, Kusama K, Abe S, et al. Relationship between dietary folate intakes, maternal plasma total homocysteine and B-vitamins during pregnancy and fetal growth in Japan. Eur J Nutr, 2007, 46(5):300–306.
14. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, et al. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet, 1995, 345(8943):149–151.
15. Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, et al. Analysis of select folate pathway genes, PAX3, and human T in a midwestern neural tube defect population. Teratology, 1999, 59(5):331–341.
16. Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, et al. Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet A, 2003, 119(2):172–176.
17. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(pt 5):379–396.
18. Brown KS, Cook M, Hoess K, Whitehead AS, Mitchell LE. Evidence that the risk of spina bifida is influenced by genetic variation at the NOS3 locus. Birth Defects Res A Clin Mol Teratol. 2004. 70(3):101–106.
19. Sun F, Flanders WD, Yang Q, Khoury MJ. A new method for estimating the risk ratio in studies using case-parental control design. Am J Epidemiol, 1998, 148(9):902–909.
20. Spielman RS, McGinnis RE, Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet, 1993, 52(3):506–516.
21. Posey DL, Khoury MJ, Mulinare J, Adams MJ Jr, Ou CY. Is mutated MTHFR a risk factor for neural tube defects? Lancet, 1996, 347(9002):686–687.
22. van der Put NM, van den Heuvel LP, Steegers-Theunissen RP, Trijbels FJ, Eskes TK, Mariman EC, et al. Decreased methylene tetrahydrofolate reductase activity due to the 677C→T mutation in families with spina bifida offspring. J Mol Med, 1996, 74(11):691–694. Erratum in: J Mol Med, 1997, 75(1):69.
23. van der Put NM, Thomas CM, Eskes TK, Trijbels FJ, Steegers-Theunissen RP, Mariman EC, et al. Altered folate and vitamin B-12 metabolism in families with spina bifida offspring. QJM, 1997, 90(8):505–510.
24. Kang SS. Treatment of hyperhomocyst(e)inemia: physiological basis. J Nutr, 1996, 126(4 Suppl):1273S–1275S.
25. Weisberg IS, Park E, Ballman KV, Berger P, Nunn M, Suh DS, et al. Investigations of a common genetic methyltransferase (BHMT) variant in betaine-homocysteine in coronary artery disease. Atherosclerosis, 2003, 167(2):205–214.
26. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol, 2000, 151(9):862–877.
27. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet, 1995, 10(1):111–113.
28. Alozie Arole CN, Puder KS, Reznar M, Eby E, Zhu BP. Folic acid awareness in Michigan, 1996–1999. Obstet Gynecol, 2003, 102(5 Pt 1):1046–1050.
29. Rampersaud E, Melvin EC, Siegel D, Mehltretter L, Dickerson ME, George TM, et al. Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects. Clin Genet, 2003, 63(3):210–214.
30. Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, Speer MC; NTD Collaborative Group. Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ Health Perspect, 2006, 114(10):1547–1552.
1. Greulich WW, Pyle SI, ed. Radiographic atlas of skeletal development of hand wrist. Second ed. Stanford, CA: Stanford University Press, 1971.
2. Tanner JM, Healy MJR, Goldstein H, Cameron N, ed. Assessment of skeletal maturity and prediction of adult height (TW3 method). 3rd ed. London: WB Saunders, 2001, 1–108.
3. Zhang A, Gertych A, Liu BJ. Automatic bone age assessment for young children from newborn to 7-year-old using carpal bones. Comput Med Imaging Graph 2007, 31(4-5):299–310.
4. Pietka E, Pospiech S, Gertych A, Cao F. Integration of computer assisted bone age assessment with clinical PACS. Comput Med Imag Grap 2002, 1–12.
5. Zhang A, Cao F, Pietka E, Liu BJ, Huang HK. Data mining for average images in a digital hand atlas. Proc SPIE Med Imag 2004, 5371:251–258.
6. Kennedy J, Eberhart RC. Particle swarm optimization. Proceedings of IEEE international conference on neural networks. Piscataway, NJ. 1995:1942–1948.
7. Eberhart RC, Kennedy J. A new optimizer using particle swarm theory. Proceedings of the sixth international symposium on micromachine and human science. Nagoya, Japan, 1995:39–43.
8. Meissner M, Schmuker M, Schneider G. Optimized Particle Swarm Optimization(OPSO) and its application to artificial neural network training. BMC Bioinformatics 2006, 7:125.
9. Liu Z, Liu J, Chen JX. Automatic bone age assessment based on PSO. Proceedings of the 1st International conference on bioinformatics and biomedical engineering. Wuhan, China. 2007: 453–455.
10. Bull RK, Edwards PD, Kemp PM, Fry S, Hughes IA. Bone age assessment: a large scale comparison of the Greulich and Pyle, and Tanner and Whitehouse (TW2) methods. Arch Dis Child 1999, 81(2):172–173.
11. Hsieh CW, Jong TL, Tiu CM. Bone age estimation based on phalanx information with fuzzy constrain of carpals. Med Biol Eng Comput 2007, 45(3):283–295.
12. Pietka E, Gertych A, Pospiech S, Cao F, Huang HK, Gilsanz V. Computer-assisted bone age assessment: image preprocessing and epiphyseal/metaphyseal ROI extraction. IEEE Trans Med Imaging 2001, 20(8):715–729.
13. Pietka BE, Po?piech S, Gertych A, Cao F, Huang HK, Gilsanz V. Computer automated approach to the extraction of epiphyseal regions in hand radiographs. J Digit Imaging 2001, 14(4):165–172.
14. Koc A, Karaoglanoglu M, Erdogan M, Kosecik M, Cesur Y. Assessment of bone ages: is the Greulich-Pyle method sufficient for Turkish boys? Pediatr Int 2001, 43(6):662–665.
15. Schmeling A, Schulz R, Danner B, R?sing FW. The impact of economic progress and modernization in medicine on the ossification of hand and wrist. Int J Legal Med 2006, 120(2):121–126.
1. Harris MJ, Juriloff DM. Mini-review: Toward understanding mechanisms of genetic neural tube defects in mice. Teratol, 1999, 60(5):292–305.
2. Milunsky A, Jick H, Jick SS, Bruell CL, MacLaughlin DS, Rothman KJ, et al. Multivitamin/folic acid supplementation in early pregnancy reduces the prevalence of neural tube defects. JAMA, 1991, 262(20): 2847–2852.
3. MRC Vitamin Study Research Group. Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet, 1991, 338(8760):131–137.
4. Centers for Disease Control and Prevention. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep, 1992, 41(RR-14):1-7. Review.
5. Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: A HuGE review. Am J Epidemiol, 2000, 151(9):862–877.
6. Morrison K, Papapetrou C, Hol FA, Mariman EC, Lynch SA, Burn J, et al. Susceptibility to spina bifida; an association study of five candidate genes. Ann Hum Genet, 1998, 62(Pt. 5):379–396.
7. Chatkupt S, Skurnick JH, Jaggi M, Mitruka K, Koenigsberger MR, Johnson WG. Study of genetics, epidemiology, and vitamin usage in familial spina bifida in the United States in the 1990s. Neurol, 1994, 44(1):65–70.
8. Guney O, Canbilen A, Konak A, Acar O. The effects of folic acid in the prevention of neural tube development defects caused by phenytoin in early chick embryos. Spine, 2003, 28(5):442–445.
9. van der Put NM, Steegers-Theunissen RP, Frosst P, Trijbels FJ, Eskes TK, van den Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet, 1995, 346(8982):1070–1071.
10. Trembath D, Sherbondy AL, Vandyke DC, Shaw GM, Todoroff K, Lammer EJ, et al. Analysis of select folate pathway genes, PAX3, and human T in a Midwesternneural tube defect population. Teratology, 1999, 59(5):331-41.
11. Elwood JM, Little J, Elwood JH. Epidemiology and control of neural tube defects. Oxford: Oxford University Press. 1992.
12. Ross SA, McCaffery PJ, Drager UC, De Luca LM. Retinoids in embryonal development. Physiol Rev, 2000, 80(3):1021–1054.
13. National Research Council. Scientific frontiers in developmental toxicology and risk assessment. Washington, D.C.: National Academy Press. 2000.
14. Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, et al. Testing for genetic associations in a spina bifida population: Analysis of the HOX gene family and human candidate gene regions implicated by mouse models of neural tube defects. Am J Med Genet, 2002, 110(3):203–207.
15. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetetrahydrofolate reductase. Nat Genet, 1995, 10(1):111–113.
16. Shields DC, Kirke PN, Mills JL, Ramsbottom D, Molloy AM, Burke H, et al. The‘‘thermolabile’’variant of methylenetetrahydrofolate reductase and neural tube defects: An evaluation of the genetic risk and the relative importance of the genotypes of the embryo and the mother. Am J Hum Genet, 1999, 64(4):1045–1055.
17. Alozie Arole CN, Puder KS, Reznar M, Eby E, Zhu BP. Folic acid awareness in Michigan, 1996–1999. Obstet Gynecol, 2003, 102(5 Pt 1):1046–1050.
18. Rampersaud E, Melvin EC, Siegel D, Mehltretter L, Dickerson ME, George TM, et al. Updated investigations of the role of methylenetetrahydrofolate reductase in human neural tube defects. Clin Genet, 2003, 63(3):210–214.
19. Morin I, Platt R, Weisberg I, Sabbaghian N, Wu Q, Garrow TA, et al. 2003. Common variant in betaine-homocysteine methyltransferase (BHMT) and risk for spina bifida. Am J Med Genet A, 2003, 119(2): 172–176.
20. Felder B, Stegmann K, Schultealbert A, Geller F, Strehl E, Ermert A, et al.Evaluation of BMP4 and its specific inhibitor NOG as candidates in human neural tube defects (NTDs). Eur J Hum Genet, 2002, 10(11):753–756.
21. Ramsbottom D, Scott JM, Molloy A, Weir DG, Kirke PN, Mills JL, et al. Are common mutations of cystathionine beta-synthase involved in the aetiology of neural tube defects? Clin Genet, 1997, 51(1):39–42.
22. Zhao R, Zhu H, Dao J, Li Z. Study on genotypes of cystathionine beta-synthase in neural tube defects. Wei Sheng Yan Jiu, 2000, 29(1):50–51.
23. Dickerson M, Joseph J, George M, Enterline DS, Melvin EC, Gilbert JR, Linney E, Speer MC, NTD Collaborative Group. CYP26A1 and RALDH2 are not implicated in the development of human neural tube defects. Am J Hum Gen, 2002, 71:469.
24. Klootwijk R, Hol FA, Wu M, Willemen JJ, Groenen P, Hamel B, et al. Genetic variation analysis of MLP, TFAP2A, and CSK in patients with neural tube defects. J Med Genet, 2003, 40(4):e43.
25. Speer MC, Rampersaud E, Melvin EC, George TM, Allen J, Floyd LE, Dickerson M, NTD Collaborative Group. Genomic screening and testing of candidate genes in human neural tube defects. International Neural Tube Defects Conference. 2003.
26. Vieira AR, Trembath D, Vandyke DC, Murray JC, Marker S, Lerner G, et al. Studies with His475Tyr glutamate carboxypeptidase II polymorphism and neural tube defects. Am J Med Genet, 2002, 111(1): 218–219.
27. Afman LA, Trijbels FJ, Blom HJ. The H475Y polymorphism in the glutamate carboxypeptidase II gene increases plasma folate without affecting the risk for neural tube defects in humans. J Nutr, 2003, 133(1):75–77.
28. Stumpo DJ, Eddy RL, Haley LL, Sait S, Shows TB, Lai WS, et al. Promoter sequence, expression, and fine chromosomal mapping of the human gene (MLP)encoding the MARCKS-like protein: Identification of neighboring and linked polymorphic loci for MLP and MACS and use in the evaluation of human neural tube defects. Genomics, 1998, 49(2):253–264.
29. Stegmann K, Boecker J, Richter B, Capra V, Finnell RH, Ngo ET, et al. A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects. Teratology, 2001, 63(5):167–175.
30. Hol FA, Geurds MP, Chatkupt S, Shugart YY, Balling R, Schrander-Stumpel CT, et al. PAX genes and human neural tube defects: An amino acid substitution in PAX1 in a patient with spina bifida. J Med Genet, 1996, 33(8):655–660.
31. Brody LC, Conley M, Cox C, Kirke PN, McKeever MP, Mills JL, et al. A polymorphism, R653Q, in the trifunctional enzyme methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase/formyltetrahydrofolate synthetase is a maternal genetic risk factor for neural tube defects: report of the Birth Defects Research Group. Am J Hum Genet, 2002, 71(5):1207–1215.
32. Stegmann K, Ziegler A, Ngo ET, Kohlschmidt N, Schr?ter B, Ermert A, et al. Linkage disequilibrium of MTHFR genotypes 677C/T-1298A/C in the German population and association studies in probands with neural tube defects (NTD). Am J Med Genet, 1999, 87(1):23–29.
33. Christensen B, Arbour L, Tran P, Leclerc D, Sabbaghian N, Platt R, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet, 1999, 84(2):151–157.
34. De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, et al. Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population. J Hum Genet, 2002, 47(6):319–324.
35. Johanning GL, Wenstrom KD, Tamura T. Changes in frequencies of heterozygous thermolabile 5,10-methylenetetrahydrofolate reductase gene in fetuses with neural tube defects. J Med Genet, 2002, 39(5):366–367.
36. Cunha AL, Hirata MH, Kim CA, Guerra-Shinohara EM, Nonoyama K, Hirata RD. Metabolic effects of C677T and A1298C mutations at the MTHFR gene in Brazilian children with neural tube defects. Clin Chim Acta, 2002, 318(1-2):139–143.
37. Gonzalez-Herrera L, Garcia-Escalante G, Castillo-Zapata I, Canto-Herrera J, Ceballos-Quintal J, Pinto-Escalante D, et al. Frequency of the thermolabile variant C677T in the MTHFR gene and lack of association with neural tube defects in the State of Yucatan, Mexico. Clin Genet, 2002, 62(5): 394–398.
38. Pietrzyk JJ, Bik-Multanowski M, Sanak M, Twardowska M. Polymorphisms of the 5,10-methylenetetrahydrofolate and the methionine synthase reductase genes as independent risk factors for spina bifida. J Appl Genet, 2003, 44(1):111–113.
39. Gutiérrez Revilla JI, Pérez Hernández F, Calvo Martín MT, Tamparillas Salvador M, Gracia Romero J. C677T and A1298C MTHFR polymorphisms in the etiology of neural tube defects in Spanish population. Med Clin (Barc), 2003, 120(12):441–445.
40. Brody LC, Baker PJ, Chines PS, Musick A, Molloy AM, Swanson DA, et al. Methionine synthase: high-resolution mapping of the human gene and evaluationas a candidate locus for neural tube defects. Mol Genet Metab, 1999, 67(4):324–333.
41. Guéant-Rodriguez RM, Rendeli C, Namour B, Venuti L, Romano A, Anello G, et al. Transcobalamin and methionine synthase reductase mutated polymorphisms aggravate the risk of neural tube defects in humans. Neurosci Lett, 2003, 344(3):189–192.
42. Wilson A, Platt R,Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab, 1999, 67(4):317–323.
43. Rogner UC, Danoy P, Matsuda F, Moore GE, Stanier P, Avner P. SNPs in the CpG island of NAP1L2: A possible link between DNA methylation and neural tube defects? Am J Med Genet, 2002, 110(3):208–214.
44. Deak KL, Boyles AL, Etchevers HC, Melvin EC, Siegel DG, Graham FL, et al. SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Hum Genet, 2005, 117(2-3):133-142.
45. Bauer KA, George TM, Enterline DS, Stottmann RW, Melvin EC, Siegel D, Samal S, Hauser MA, Klingensmith J, Nye JS, Speer MC, Neural Tube Defects Collaborative Group. A novel mutation in the gene encoding noggin is not causative in human neural tube defects. Neurogenet, 2002, 16(1):65–71.
46. Chatkupt S, Hol FA, Shugart YY, Geurds MP, Stenroos ES, Koenigsberger MR, et al. Absence of linkage between familial neural tube defects and PAX3 gene. J Med Genet, 1995, 32(3):200–204.
47. Volcik KA, Blanton SH, Kruzel MC, Townsend IT, Tyerman GH, Mier RJ, et al. Testing for genetic associations with the PAX gene family in a spina bifida population. Am J Med Genet, 202, 110(3):195–202.
48. Joosten PH, Toepoel M, Mariman EC, Van Zoelen EJ. Promoter haplotype combinations of the platelet-derived growth factor alpha-receptor gene predispose to human neural tube defects. Nat Genet, 2001, 27(2):215–217.
49. Joosten PH, Toepoel M, van Oosterhout D, Afink GB, van Zoelen EJ. A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors. Biochim Biophys Acta, 2002, 1588(3):254–260.
50. De Marco P, Calevo MG, Moroni A, Merello E, Raso A, Finnell RH, et al. Reduced folate carrier polymorphism (80A→G) and neural tube defects. Eur J Hum Genet, 2003, 11(3):245–252.
51. Shaw GM, Lammer EJ, Zhu H, Baker MW, Neri E, Finnell RH. Maternal periconceptional vitamin use, genetic variation of infant reduced folate carrier (A80G), and risk of spina bifida. Am J Med Genet, 2002, 108(1):1–6.
52. Vargas FR, Roessler E, Gaudenz K, Belloni E, Whitehead AS, Kirke PN, et al. Analysis of the human Sonic Hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly. Hum Genet, 1998, 102(4):387–392.
53. Kirillova I, Novikova I, AugéJ, Audollent S, Esnault D, Encha-Razavi F, et al. Expression of the sonic hedgehog gene in human embryos with neural tube defects. Teratology, 2000, 61(5):347–354.
54. Zhu H, Barber R, Shaw GM, Lammer EJ, Finnell RH. Is sonic hedgehog (SHH) a candidate gene for spina bifida? A pilot study. Am J Med Genet A, 2003, 117(1):87–88.
55. Heil SG, Van der Put NM, Waas ET, den Heijer M, Trijbels FJ, Blom HJ. Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab, 2001, 73(2):164–172.
56. Shields DC, Ramsbottom D, Donoghue C, Pinjon E, Kirke PN, Molloy AM, et al. Association between historically high frequencies of neural tube defects and the human T homologue of moute T (Brachyrury). Am J Med Genet, 2000, 92(3):206–211.
57. Richter B, Schultealbert AH, Koch MC. Human T and risk for neural tube defects. J Med Genet, 2000, 39(3):E14.
58. Afman LA, Lievers KJ, van der Put NM, Trijbels FJ, Blom HJ. Single nucleotide polymorphisms in the transcobalamin gene: Relationship with transcobalamin concentrations and risk for neural tube defects. Eur J Hum Genet, 2002, 10(7):433–438.
59. Benz LP, Swift FE, Graham FL, Enterline DS, Melvin EC, Hammock P, Gilbert JR, Speer MC, Bassuk AG, Kessler JA, George TM, and the NTD Collaborative Group. TERC is not a major gene in human neural tube defects. Birth Defects Res A: Clin Molec Teratol, 2004, 70(8):531–533.
60. Volcik KA, Shaw GM, Zhu H, Lammer EJ, Finnell RH. Risk factors for neural tube defects: Associations between uncoupling protein 2 polymorphisms and spina bifida. Birth Defects Res A Clin Molec Teratol, 2003, 67(3):158–161.
61. Newton R, Stanier P, Loughna S, Henderson DJ, Forbes SA, Farrall M, et al. Linkage analysis of 62 X-chromosomal loci excludes the X chromosome in an Icelandic family showing apparent X-linked recessive inheritance of neural tube defects. Clin Genet, 1994, 45(5):241–249.
62. Brown LY, Hodge SE, Johnson WG, Guy SG, Nye JS, Brown S. Possible association of NTDs with a polyhistidine tract polymorphism in the ZIC2 gene. Am J Med Genet, 2002, 108(2):128–131.
63. Zhu H, Junker WM, Finnell RH, Brown S, Shaw GM, Lammer EJ, et al. Lack of association between ZIC2 and ZIC3 genes and the risk of neural tube defects (NTDs) in Hispanic populations. Am J Med Genet A, 2003, 116(4):414–415.
64. Carrel T, Herman GE, Moore GE, Stanier P. Lack of mutations in ZIC3 in three families with neural tube defects. Am J Med Genet, 2001, 98(3):283–285.
1. Copp AJ, Greene ND, Murdoch JN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003, 4(10):784–93.
2. Li Z, Ren A, Zhang L, Ye R, Li S, Zheng J, et al. Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China. Birth Defects Res A Clin Mol Teratol, 2006, 76(4):237–240.
3. Lalouel JM, Morton NE, Jackson J. Neural tube malformations: complex segregation analysis and calculation of recurrence risks. J Med Genet, 1979, 16(1):8–13.
4. Van Allen MI, Kalousek DK, Chernoff GF, Juriloff D, Harris M, McGillivray BC, et al. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet, 1993, 47(5):723–743. Review.
5. Strong LC, Hollander WF. Hereditary loop-tail in the house mouse. J Hered, 1949, 40:329–334.
6. Rachel RA, Murdoch JN, Beermann F, Copp AJ, Mason CA. Retinal axonmisrouting at the optic chiasm in mice with neural tube closure defects. Genesis, 2000, 27(1):32–47.
7. Curtin JA, Quint E, Tsipouri V, Arkell RM, Cattanach B, Copp AJ, et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr Biol, 2003, 13(13):1129–1133.
8. Lu X, Borchers AG, Jolicoeur C, Rayburn H, Baker JC, Tessier-Lavigne M. PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates. Nature, 2004, 430(6995):93–98.
9. Hamblet NS, Lijam N, Ruiz-Lozano P, Wang J, Yang Y, Luo Z, et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development, 2002, 129(24):5827–5838.
10. Murdoch JN, Rachel RA, Shah S, Beermann F, Stanier P, Mason CA, et al. Circletail, a new mouse mutant with severe neural tube defects: chromosomal localization and interaction with the loop-tail mutation. Genomics, 2001, 78(1–2):55–63.
11. Wallingford JB, Harland RM. Xenopus Dishevelled signaling regulates both neural and mesodermal convergent extension: parallel forces elongating the body axis. Development, 2001, 128(13):2581–2592.
12. Strutt DI. The asymmetric subcellular localization of components of the planar polarity pathway. Semin Cell Dev Biol, 2002, 13(3):225–231.
13. Tree DR, Ma D, Axelrod JD. A three-tiered mechanism for regulation of planar cell polarity. Semin Cell Dev Biol, 2002, 13(3):217–224.
14. Mlodzik M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet, 2002, 18(11):564–571.Review.
15. Das G, Jenny A, Klein TJ, Eaton S, Mlodzik M. Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development, 2004, 131(18):4467–4476.
16. Jenny A, Reynolds-Kenneally J, Das G, Burnett M, Mlodzik M. Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding. Nat Cell Biol, 2005, 7(7):691–697.
17. Wang J, Hamblet NS, Mark S, Dickinson ME, Brinkman BC, Segil N, et al. Dishevelled genes mediate a conserved mammalian PCP pathway to regulate convergent extension during neurulation. Development, 2006, 133(9):1767–1778.
18. Hamblet NS, Lijam N, Ruiz-Lozano P, Wang J, Yang Y, Luo Z, et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development, 2002, 129(24):5827–5838.
19. Wallingford JB, Harland RM. Neural tube closure requires Dishevelled-dependent convergent extension of the midline. Development, 2002, 129(24):5815–5825.
20. Heisenberg CP, Tada M, Rauch GJ, Saúde L, Concha ML, Geisler R, et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature, 2000, 405(6782):76–81.
21. Tissir F, De-Backer O, Goffinet AM, Lambert de Rouvroit C. Developmental expression profiles of Celsr (Flamingo) genes in the mouse. Mech Dev, 2002, 112(1–2):157–160.
22. Torban E, Kor C, Gros P. Van Gogh-like2 (Strabismus) and its role in planar cell polarity and convergent extension in vertebrates. Trends Genet, 2004, 20(11):570–577.
23. Goto T, Keller R. The planar cell polarity gene strabismus regulates convergence and extension and neural fold closure in Xenopus. Dev Biol, 2002, 247(1):165–181.
24. Bastock R, Strutt H, Strutt D. Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development, 2003, 130(13):3007–3014.
25. Jenny A, Darken RS, Wilson PA, Mlodzik M. Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling. EMBO J, 2003, 22(17):4409–4420.
26. Murdoch JN, Doudney K, Paternotte C, Copp AJ, Stanier P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum Mol Genet, 2001, 10(22):2593–2601.
27. Katoh Y, Katoh M. Comparative genomics on Vangl1 and Vangl2 genes. Int J Oncol, 2005, 26(5):1435–1440.
28. Torban E, Wang HJ, Groulx N, Gros P. Independent mutations in mouse Vangl2 that cause neural tube defects in looptail mice impair interaction with members of the Dishevelled family. J Biol Chem, 2004, 279(50):52703–52713.
29. Liu J, Qi J, Zhu J, Zhang L, Liang Y, Ning Q, Luo X. Effects of retinoic acid on the expressions of Vangl1 and Vangl2 in mouse fetuses. J Neurogenet, 2008 (In press).
30. Hotta K, Takahashi H, Asakura T, Saitoh B, Takatori N, Satou Y, et al. Characterization of Brachyury–downstream notochord genes in the Ciona intestinalis embryo. Dev Biol, 2000, 224(1):69–80.
31. Wallingford JB, Goto T, Keller R, Harland RM. Cloning and expression ofXenopus Prickle, an orthologue of a Drosophila planar cell polarity gene. Mech Dev, 2002, 116(1–2):183–186.
32. Takeuchi M, Nakabayashi J, Sakaguchi T, Yamamoto TS, Takahashi H, Takeda H, et al. The prickle–related gene in vertebrates is essential for gastrulation cell movements. Curr Biol, 2003, 13(8):674–679.
33. Veeman MT, Slusarski DC, Kaykas A, Louie SH, Moon RT. Zebrafish prickle, a modulator of noncanonical Wnt/Fz signaling, regulates gastrulation movements. Curr Biol, 2003, 13(8):680–685.
34. Povelones M, Nusse R. The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J, 2005, 24(19):3493–3503.
35. Carron C, Pascal A, Djiane A, Boucaut JC, Shi DL, Umbhauer M. Frizzled receptor dimerization is sufficient to activate the Wnt/beta-catenin pathway. J Cell Sci, 2003, 116(Pt 12):2541–2550.
36. Fanto M, McNeill H. Planar polarity from flies to vertebrates. J Cell Sci, 2004, 117(Pt 4):527–533.
37. Bilder D, Perrimon N. Localization of apical epithelial determinants by the basolateral PDZ protein Scribble. Nature, 2000, 403(6770):676–680.
38. Schwarz-Romond T, Asbrand C, Bakkers J, Kühl M, Schaeffer HJ, Huelsken J, et al. The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev, 2002, 16(16):2073–2084.
39. Strutt DI, Weber U, Mlodzik M. The role of RhoA in tissue polarity and Frizzled signalling. Nature, 1997, 387(6630):292–295.
40. Winter CG, Wang B, Ballew A, Royou A, Karess R, Axelrod JD, et al. DrosophilaRho-associated kinase (Drok) links Frizzled-mediated planar cell polarity signaling to the actin cytoskeleton. Cell, 2001, 105(1):81–91.
41. Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, et al. Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development, 2001, 128(15):2953–2962.