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The phenotype of the genetic polydactyly/arhinencephaly mouse (Pdn/Pdn) is similar to Greig cephalopolysyndactyly syndrome (GCPS), which is induced by mutation of GLI3. Suppression of Gli3 gene expression has been observed in Pdn/Pdn. Thus, the gene responsible for Pdn/Pdn has been considered to be Gli3. Recently, the mutation point was demarcated, that is, a transposon was inserted into intron 3 of the Gli3 gene in the Pdn mouse. Forward and reverse primers were constructed in intron 3 near the insertion point. A forward primer in the long terminal repeat region of the transposon was also constructed. Now we can discriminate +/+, Pdn/+, Pdn/Pdn embryos from the PCR products. After genotyping of the Pdn embryos, Gli3 and other correlated gene expressions, such as sonic hedgehog (Shh), Bmp-2, Bmp-4, ptc-1, were analyzed by real-time PCR method. Gli3 gene expression in Pdn/Pdn was suppressed to 20-30% of +/+, and that in Pdn/+ was about 60% of +/+ through all the embryonic and neonatal periods examined. As Shh has been considered to be an antagonist of Gli3, Shh expression was analyzed, and a difference among genotypes was observed only on day 9 of gestation. We could not detect any alterations among genotypes in other gene expressions examined. Gli3 and Shh gene expression were also analyzed on day 9 by whole-mount in situ hybridization in the +/+ and Pdn/Pdn embryos. Neuroectoderm was positive by Gli3 probe in +/+ but not in Pdn/Pdn. Notochord, floor plate and prechordal mesoderm were positive by Shh probe both in +/+ and Pdn/Pdn embryos, but ectopic and/or over-expression of Shh were not observed in Pdn/Pdn embryos. 相似文献
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The gene responsible for the polydactyly/arhinencephaly (Pdn/Pdn) mouse, which exhibits polysyndactyly and arhinencephaly and has a 13.2% risk of neural tube defects (NTD), has been identified as Gli3. Ochratoxin A (OTA) is a teratogen causing NTD in mice. When Pdn/Pdn embryos were exposed to 2 mg/kg of OTA on day 7.5, the incidence of NTD in Pdn/Pdn fetuses increased to 51.6%. Pre-treatment with folinic acid (FA), metabolically the most active form of folic acid, before OTA-treatment decreased the incidence of NTD to 20.8%. We investigated the effect of OTA and FA on gene expression in day 9 embryos using whole-mount in situ hybridization and real-time PCR. Over-expression of Fgf8 was observed at the anterior neural ridge (ANR) in the non-treated Pdn/Pdn. Over-expression at the ANR expanded in the OTA-treated Pdn/Pdn, and it was ameliorated by pretreatment with FA. Emx2 signal was observed in the dorsal forebrain in the non-treated +/+, but disappeared in the OTA-treated +/+, and was recovered by FA. The Emx2 signal was pale and the expression amount was depressed in the non-treated and OTA-treated Pdn/Pdn embryos. It was suggested that down-regulation of Gli3 induced the over-expression of Fgf8 at the ANR, that OTA treatment accelerated the over-expression, and that pretreatment with FA ameliorated the OTA-induced over-expression of Fgf8 in the Pdn/Pdn. It was also suggested that down-regulation of Gli3 induced the down-regulation of Emx2 in the Pdn/Pdn. It was further speculated that the over-expression of Fgf8 at the ANR and down-regulation of Emx2 in the dorsal forebrain may contribute to NTD induction. 相似文献
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目的:研究髓母细胞瘤患者中发现的Supressor of Fused(Sufu)的突变位点与Sonic Hedgehog(Shh)信号通路异常激活之间的联系,从而揭示其与肿瘤生长发展之间的关系。方法:构建Sufu突变位点的表达质粒,通过定量PCR、蛋白免疫印迹实验检测Sufu突变体对Sufu-/-细胞内源性Gli1表达水平的影响;通过免疫共沉淀检测Sufu突变体蛋白与Gli1的结合情况;通过MTT实验检测Sufu突变体对人髓母细胞瘤细胞(DAOY)生长增殖的影响。结果:定量PCR和蛋白免疫印迹实验发现,过表达Sufu的错义突变体(突变位点H87R)的Sufu-/-细胞中内源性Gli1表达水平接近于过表达野生型Sufu的Sufu-/-细胞,而过表达3个截短突变体(突变位点R146X、R299X、W430X)Sufu-/-细胞中内源性Gli1表达水平相比于野生型明显增高。正常情况下野生型Sufu可以和Gli1蛋白结合,免疫共沉淀实验发现Sufu的突变体都不同程度地破坏了与Gli1蛋白的结合;蛋白周转速率实验发现Sufu的突变体可以通过蛋白酶体途径降解;MTT实验发现Sufu突变体失去了抑制DAOY细胞生长增殖的能力。结论:髓母细胞瘤患者身上观测到的Sufu突变位点可以驱动肿瘤的形成和生长,并通过细胞功能实验证实了Sufu通过结合Gli蛋白从而抑制其功能。 相似文献
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目的 Hedgehog信号通路的异常活化与多种肿瘤的发生、发展关系密切,Gli是该通路的重要组成部分.本研究分析Gli抑制剂GANT61对人食管鳞癌细胞OE21和KYSE-30生长抑制作用,并探讨其抗肿瘤作用机制.方法 采用不同浓度GANT61处理OE21和KYSE-30细胞,MTS法检测细胞活力;实时荧光定量PCR检测GANT61作用于OE21和KYSE 30细胞后对Gli1和Gli2 mRNA的影响;蛋白质印迹法观察GANT61作用于OE21和KYSE-30细胞后对Gli1、Gli2和Cyclin D1蛋白表达的影响.Transwell侵袭实验观察GANT61作用于OE21和KYSE-30细胞后对侵袭能力的影响.结果 GANT61对OE21和KYSE-30细胞有明显的生长抑制作用并且呈剂量依赖性,MTS显示GANT61作用于OE21和KYSE-30细胞72 h的IC50值分别为4.7和8.2 μmol/L.GANT61可显著下调OE21细胞Gli1(z=-1.98,P=0.04)和Gli2(z=-1.99,P=0.04)mRNA以及Gli1、Gli2和Cyclin D1蛋白表达.GANT61可显著下调KYSE-30细胞Gli1(z=-3,58,P<0.001)和Gli2(z=-2.282,P=0.004)mRNA以及Gli1、Gli2和Cyclin D1蛋白表达.Transwell侵袭实验显示,OE21细胞GANT61组穿膜细胞数为53±6.78,较DMSO组的140±11.02减少,t=12.888,P<0.001;KYSE-30细胞GANT61组穿膜细胞数为58.2±7.59,较DMSO组的133.4±9.37减少,t=11.452,P<0.001.结论 GANT61可以通过下调Gli1和Gli2的表达显著抑制OE21和KYSE-30细胞的细胞生长和侵袭能力,Gli可能成为抑制食管鳞癌细胞增殖和转移的新的分子靶点. 相似文献