Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb-/- mouse embryos occurs in the absence of an endodermal plug.
Formation of duodenal atresias in fibroblast growth factor receptor 2IIIb-/- mouse embryos occurs in the absence of an endodermal plug.
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DOI：
10.1016/j.jpedsurg.2012.02.001
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发表时间：
2012-07
影响因子：
2.4
通讯作者：
Nichol PF
中科院分区：
文献类型：
--
作者：
Botham RA;Franco M;Reeder AL;Lopukhin A;Shiota K;Yamada S;Nichol PF
人类的十二指肠闭锁被假设是由于内胚层栓形成后，十二指肠腔未能再通。最近，成纤维细胞生长因子受体2基因的突变已被证明会导致小鼠十二指肠闭锁缺陷（Fgfr 2 IIIb）。然而，在大鼠中的研究表明，鼠类在正常的十二指肠发育过程中不会形成内胚层栓。这些数据使我们假设，小鼠能够在没有内胚层栓的情况下形成十二指肠闭锁。为了验证这一假设，我们研究了野生型和Fgfr 2 IIIb-/-胚胎的十二指肠发育。从胚胎第10.5天（E）至E14.5天之间的Fgfr 2 IIIb-/-和野生型胚胎中制备石蜡切片，用于苏木精和伊红、E-钙粘蛋白或末端脱氧核苷酸转移酶介导的X-dUTP缺口末端标记（TUNEL）染色。对切片进行拍照，并使用Adobe Photoshop和Amira Visage软件重建成三维显示。正常小鼠的十二指肠不形成内胚层栓，尽管在E14.5时胃的幽门区确实形成了栓。Fgfr 2 IIIb-/-胚胎在E10.5时在十二指肠区域经历显著的细胞凋亡，随后在E11.5时闭锁前体中的内胚层消失。此后，闭锁前体的中胚层在接下来的2天内在没有进一步细胞凋亡的情况下内卷。有趣的是，在十二指肠闭锁形成过程中的任何时候都没有观察到内胚层栓。这些结果表明，Fgfr 2 IIIb-/-模型中的十二指肠闭锁并非由上皮栓的持续存在引起。相反，它似乎是由于细胞凋亡导致的内胚层在发育早期的损失。
Duodenal atresia in humans has been hypothesized to arise from a failure of the duodenal lumen to recanalize after formation of an endodermal plug. Recently, mutations in the Fibroblast Growth Factor Receptor 2 gene have been shown to cause atretic defects of the duodenum in mice (Fgfr2IIIb). However, work in rats suggests that murine species do not form an endodermal plug during normal duodenal development. These lines of data led us to hypothesize that mice are able to form a duodenal atresia in the absence of an endodermal plug. To test this hypothesis we examined duodenal development in wild-type and Fgfr2IIIb-/- embryos. Paraffin sections were generated for either hematoxylin and eosin, E-cadherin or terminal deoxynucleotidyl transferase mediated X-dUTP nick end labeling (TUNEL) staining from Fgfr2IIIb-/- and wild-type embryos between Embryonic Days (E) 10.5 and E14.5. Sections were photographed and reconstructed into 3-dimensional display using Adobe Photoshop and Amira Visage software. Normal mouse duodenum does not form an endodermal plug, although a plug does form in the pyloric region of the stomach at E14.5. Fgfr2IIIb-/- embryos experience significant apoptosis in the duodenal region at E10.5, followed by the disappearance of the endoderm in the atretic precursor by E11.5. Thereafter, the mesoderm of the atretic precursor involutes over the next 2 days in the absence of further apoptosis. Interestingly, an endodermal plug was not observed at any point during the formation of a duodenal atresia. These results suggest that duodenal atresia in the Fgfr2IIIb-/- model does not arise from persistence of an epithelial plug. Rather it appears to result from the loss of the endoderm due to apoptosis very early in development.
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