Sensitivity to cadmium-chloride-induced forelimb ectrodactyly is independent of the p53 gene-dosage in the C57BL/6J mouse.
Sensitivity to cadmium-chloride-induced forelimb ectrodactyly is independent of the p53 gene-dosage in the C57BL/6J mouse.
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C57BL/6J 小鼠对氯化镉诱导的前肢外指畸形的敏感性与 p53 基因剂量无关。
DOI：
10.1002/bdra.20652
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Collins,MichaelD
中科院分区：
文献类型：
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作者：
Elsaid,AhmedF;Koriem,KhaledMM;Collins,MichaelD
p53通路在细胞凋亡、成骨细胞分化、骨骼发育和致畸敏感性的调控中发挥重要作用。在易感小鼠品系妊娠第9天给予氯化镉（CdCl2）可通过未知机制导致一定比例胎儿轴后前肢外指畸形。本研究检验了p53基因剂量可能影响cdcl2诱导的前肢外指畸形发生率或严重程度的假设。方法在C57BL/6J基因背景下，已知对CdCl2诱导的前肢外指畸形敏感的sheterozygousp53阴性雌性小鼠与杂合雄性小鼠交配，然后在胚胎日（ED） 9时单次腹腔注射CdCl2（4 mg × kg - 1）。在ED10收集胚胎和胎儿，使用从卵黄囊中分离的DNA进行基因分型，检查肢体芽中细胞死亡的模式，或在ED18收集胚胎和胎儿，检查肢体畸形。结果在野生型和杂合型胚肢芽中，CdCl2诱导的凋亡涉及间充质细胞和顶端外胚层脊（AER），而在纯合型胚肢芽中，CdCl2诱导的凋亡主要局限于顶端外胚层脊。不同p53基因型胚胎前肢畸形发生率及严重程度无差异。结论尽管CdCl2可诱导发育中的肢体芽中p53依赖性（在间质中）和p53非依赖性（在AER中）细胞死亡，但在研究时间点，CdCl2诱导的触电与p53基因剂量无关。出生缺陷研究（A部分）2010。©2010 Wiley‐Liss, Inc。
BACKGROUNDThep53pathway plays an important role in the regulation of apoptosis, osteoblast differentiation, skeletal development, and teratogenic sensitivity. The administration of cadmium chloride (CdCl2) on gestational day 9 in susceptible mouse strains causes postaxial forelimb ectrodactyly in a percentage of fetuses through unknown mechanisms. In this study, the hypothesis that thep53gene dosage might affect the incidence or severity of CdCl2–induced forelimb ectrodactyly was examined.METHODSHeterozygousp53‐null female mice, on the C57BL/6J background known to be sensitive to CdCl2‐induced forelimb ectrodactyly, were mated with heterozygous males and then treated with a single intraperitoneal (ip) dose of CdCl2(4 mg × kg−1) at embryonic day (ED) 9. Embryos and fetuses, genotyped using DNA isolated from the yolk sacs, were collected at ED10 and examined for the pattern of cell death in the limb buds or collected at ED18 and examined for limb malformations.RESULTSIn the wild type and heterozygousp53embryonic limb buds, CdCl2‐induced apoptosis involved mesenchymal cells as well as the apical ectodermal ridge (AER), whereas CdCl2‐induced apoptosis was restricted mainly to the AER in the homozygousp53‐null limb buds. No difference in the incidence or severity of forelimb ectrodactyly in the embryos of differentp53genotypes was observed.CONCLUSIONDespite the fact that CdCl2induced both p53‐dependent (in the mesenchyme) and p53‐independent (in the AER) cell death in the developing limb bud, CdCl2‐induced ectrodactyly was independent of thep53gene dosage at the studied time point. Birth Defects Research (Part A) 2010. © 2010 Wiley‐Liss, Inc.