Hajduk Piotr, May Alison, Puri Prem, Murphy Paula
School of Natural Sciences, Trinity College Dublin, Dublin, Ireland.
Birth Defects Res B Dev Reprod Toxicol. 2012 Apr;95(2):175-83. doi: 10.1002/bdrb.21002. Epub 2012 Feb 6.
The notochord has important structural and signaling properties during vertebrate development with key roles in patterning surrounding tissues, including the foregut. The adriamycin mouse model is an established model of foregut anomalies where exposure of embryos in utero to the drug adriamycin leads to malformations including oesophageal atresia and tracheoesophageal fistula. In addition to foregut abnormalities, treatment also causes branching, displacement, and hypertrophy of the notochord. Here, we explore the hypothesis that the notochord may be a primary target of disruption leading to abnormal patterning of the foregut by examining notochord position and structure in early embryos following adriamycin exposure. Treated (n = 46) and control (n = 30) embryos were examined during the crucial period when the notochord normally delaminates away from the foregut endoderm (6-28 somite pairs). Transverse sections were derived from the anterior foregut and analyzed by confocal microscopy following immunodetection of extracellular matrix markers E-cadherin and Laminin. In adriamycin-treated embryos across all stages, the notochord was abnormally displaced ventrally with prolonged attachment to the foregut endoderm. While E-cadherin was normally detected in the foregut endoderm with no expression in the notochord of control embryos, treated embryos up to 24 somites showed ectopic notochordal expression indicating a change in characteristics of the tissue; specifically an increase in intracellular adhesiveness, which may be instrumental in structural changes, affecting mechanical and signaling properties. This is consistent with disruption of the notochord leading to altered signaling to the foregut causing abnormal patterning and congenital foregut malformations.
脊索在脊椎动物发育过程中具有重要的结构和信号特性，在包括前肠在内的周围组织模式形成中发挥关键作用。阿霉素小鼠模型是一种已确立的前肠异常模型，子宫内胚胎暴露于阿霉素会导致包括食管闭锁和气管食管瘘在内的畸形。除了前肠异常外，该处理还会导致脊索分支、移位和肥大。在此，我们通过检查阿霉素暴露后早期胚胎中的脊索位置和结构，探讨脊索可能是导致前肠异常模式形成的主要破坏靶点这一假说。在脊索正常从前肠内胚层分层离开的关键时期（6 - 28 体节对），对处理组（n = 46）和对照组（n = 30）胚胎进行检查。从前肠前部获取横切面，并在对细胞外基质标记物 E - 钙黏蛋白和层粘连蛋白进行免疫检测后，通过共聚焦显微镜进行分析。在所有阶段的阿霉素处理胚胎中，脊索异常地向腹侧移位，并与前肠内胚层长时间附着。虽然在对照组胚胎的前肠内胚层中正常检测到 E - 钙黏蛋白，而在脊索中无表达，但在多达 24 体节的处理胚胎中，脊索出现异位表达，表明组织特征发生了变化；具体表现为细胞内黏附性增加，这可能有助于结构变化，影响机械和信号特性。这与脊索的破坏导致向前肠的信号改变，从而引起异常模式形成和先天性前肠畸形是一致的。
