Comparative molecular pathology of cadmium- and all-trans-retinoic acid-induced postaxial forelimb ectrodactyly.
Comparative molecular pathology of cadmium- and all-trans-retinoic acid-induced postaxial forelimb ectrodactyly.
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DOI：
10.1016/j.taap.2007.06.005
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发表时间：
2007-11
影响因子：
3.8
通讯作者：
X. Liao;Grace S Lee;Hirohito Shimizu;M. Collins
中科院分区：
文献类型：
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作者：
X. Liao;Grace S Lee;Hirohito Shimizu;M. Collins
氯化镉（CdCl2）和全反式维甲酸（RA）在C57BL/6N小鼠早期肢体发育过程中可诱导轴后前肢外指畸形，同时给药可产生协同反应，提示该缺陷存在共同的最终途径。在本研究中，在GD 9.5治疗后的不同时间点收集胚胎的前肢芽，这些胚胎被给予高剂量的cdcl2或RA，或低剂量的两种药物联合治疗，并检查细胞凋亡，增殖和模式基因。在发育中的肢体芽中检测到的一些细胞扰动对于两种致畸剂是相似的，而其他的变化则是每种致畸剂所特有的。例如，在12和18 h， cdcl2处理增加了顶端外胚层脊（AER）下间质凋亡细胞，而RA则导致AER和近端间质凋亡。此外，联合低剂量治疗在所有三个区域协同增加细胞死亡。cdcl2和低剂量联合处理在12 h时抑制了间充质细胞的增殖，这与诱导p21cip1和抑制phospho-c-Jun有关。相反，RA不抑制间质增殖，不诱导p21cip1表达或改变c-Jun磷酸化。所有三个治疗组都显示出远端软骨形成中心模式的延迟，正如Sox9表达所表明的那样。AER标记物Fgf8和Fgf4以及参与维持上皮-间质相互作用的间质标记物Msx1的表达也普遍受到抑制。总的来说，我们假设了一个模型，其中肢体模式可以被外胚层和中胚层的损伤所干扰。
Cadmium chloride (CdCl2) and all-trans-retinoic acid (RA) induce postaxial forelimb ectrodactyly in C57BL/6N mice when administered during early limb development, and co-administration yields a synergistic response suggesting a common final pathway to the defect. In the current study, forelimb buds from embryos given high maternal teratogenic doses of CdCl2or RA, or the combination of both agents at low doses were collected at various time points after treatment on GD 9.5 and examined for cellular apoptosis, proliferation, and patterning genes. Some cellular perturbations detected in the developing limb bud were similar for both teratogens, whereas other alterations were unique to each agent. For example, at 12 and 18 h, CdCl2treatment increased apoptotic cells in the mesenchyme underneath the apical ectodermal ridge (AER), whereas RA caused apoptosis in the AER and proximal mesenchyme. Further, the combined low-dose treatment increased cell death synergistically in all three regions. CdCl2and the low-dose combined treatment inhibited mesenchymal proliferation at 12 h, which was associated with induction of p21cip1and inhibition of phospho-c-Jun. In contrast, RA did not inhibit mesenchymal proliferation and did not induce p21cip1expression or change c-Jun phosphorylation. All three treatment groups showed a delay in the patterning of distal chondrogenesis centers as indicated by Sox9 expression. There was also common inhibition in the expression of AER markers, Fgf8 and Fgf4, and the mesenchymal marker Msx1 involved in the maintenance of epithelial–mesenchymal interactions. Collectively, a model is hypothesized where limb patterning can be perturbed by insults to both ectoderm and mesoderm.