Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid-induced forelimb ectrodactyly.
Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid-induced forelimb ectrodactyly.
复制标题
外胚层和中胚层基因表达定位的改变与视黄酸诱导的前肢外指畸形的小鼠品系差异有关。
DOI：
10.1002/bdra.20358
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发表时间：
2007
期刊：
影响因子：
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通讯作者：
Collins,MichaelD
中科院分区：
文献类型：
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作者：
Shimizu,Hirohito;Lee,GraceS;Beedanagari,SudheerR;Collins,MichaelD
背景数字缺陷或融合作为一种致畸反应在人类中有很好的记录，并在各种小鼠模型中进行了深入研究。母亲暴露于过量的全反式维甲酸（RA）在妊娠第9.5天诱导轴后缺趾（数字损失）在小鼠C57 BL/6 N株，但不是在SWV/Fnn strain. METHODS全安装原位杂交被用来检查在转录水平的差异表达的肢体图案基因的两个小鼠品系之间的母体暴露于致畸水平的RA。检测到表达改变的基因后，评价其他共表达基因或评估下游基因。在母体给予RA后的C57 BL/6 N肢芽中，在AER前后部注射RA数小时内观察到基因特异性扰动。（顶端外胚层嵴）（Fgf 8，Dlx 3，Bmp 4，Sp 8，而不是Dlx 2或p63），而这些基因在SWV/Fnn肢芽中正常表达。此外，尽管RA在给药后12小时内引起菌株之间Shh表达的可比较的降低，但一些Shh下游基因的表达存在差异（例如，Gli 1，Ptc和Hoxd 13），而其他人则没有（例如，Fgf 4，Bmp 4，andGremlin）.结论提示AER前体和中胚层的基因表达改变参与了轴后趾缺失的发病机制，并且由于AER前体的改变在事件的时间序列中发生相对较早，这些变化是畸形的起始因素的候选者。出生缺陷研究（A部分），2007年。© 2007 Wiley利斯公司
BACKGROUNDDefects in digit number or fusion as a teratogenic response are well documented in humans and intensively studied in various mouse models. Maternal exposure to excess levels of all‐trans‐retinoic acid (RA) at gestational day 9.5 induces postaxial ectrodactyly (digit loss) in the murine C57BL/6N strain but not in the SWV/Fnn strain.METHODSWhole‐mountin situhybridization was used to examine the differential expression of limb patterning genes at the transcriptional level between the two mouse strains following the maternal exposure to a teratogenic level of RA. The detection of a gene with altered expression was followed by either the evaluation of other genes that were synexpressed or with an assessment of downstream genes.RESULTSIn the C57BL/6N limb bud following maternal RA administration, gene‐specific perturbations were observed within hours of the RA injection in the posterior pre‐AER (apical ectodermal ridge) (Fgf8,Dlx3,Bmp4,Sp8, but notDlx2orp63), whereas these genes were normally expressed in the SWV/Fnn limb bud. Furthermore, although RA caused comparable reductions ofShhexpression between the strains in the 12 h after administration, someShhdownstream genes were differentially expressed (e.g.,Gli1,Ptc, andHoxd13), whereas others were not (e.g.,Fgf4,Bmp4,andGremlin).CONCLUSIONSIt is proposed that altered gene expression in both pre‐AER and mesoderm is involved in the pathogenesis of postaxial digit loss, and that because the alterations in the pre‐AER occur relatively early in the temporal sequence of events, those changes are candidates for an initiating factor in the malformation. Birth Defects Research (Part A) 2007. © 2007 Wiley‐Liss, Inc.