Hirashima Masanori, Sano Keigo, Morisada Toru, Murakami Kyoko, Rossant Janet, Suda Toshio
The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Dev Biol. 2008 Apr 1;316(1):149-59. doi: 10.1016/j.ydbio.2008.01.023. Epub 2008 Jan 31.
We previously identified apoptosis stimulating protein of p53 (Aspp1) as an endothelial-specific gene functioning in mouse embryogenesis. To investigate the in vivo role of Aspp1, we generated Aspp1 knockout mice by targeted disruption. Aspp1(-/-) embryos showed subcutaneous edema and disorganized lymphatic vasculature. Morphological changes in lymphatic endothelial cells and isolated lymphatic islands were detected in Aspp1(-/-) embryos. Lymphangiography by injecting dye subcutaneously into the embryonic forelimb showed defective lymphatic drainage function and obstruction in collecting lymphatic vessels of Aspp1(-/-) embryos. Interestingly, Aspp1(-/-) adult mice resolved these lymphatic functional defects seen during embryogenesis, but lymphangiography in Aspp1(-/-) adult mice revealed abnormal patterns in collecting lymphatic vessels. Since Aspp proteins reportedly enhance apoptotic activity of p53, we asked whether p53 deficiency also affected lymphatic vessel development. Analysis of p53 knockout or Aspp1; p53 double knockout mice showed that p53 loss did not affect lymphatic vessels. These results indicate that Aspp1 plays a crucial role in the initial assembly and function of lymphatic vessels during mouse development in a p53-independent manner. Here we report novel lymphatic vascular phenotypes in Aspp1(-/-) mice; subcutaneous edema detected only during embryogenesis, delayed lymphatic vessel formation, and mispatterned collecting lymphatic vessels.
我们之前将p53凋亡刺激蛋白（Aspp1）鉴定为在小鼠胚胎发育中发挥作用的内皮特异性基因。为了研究Aspp1在体内的作用，我们通过靶向破坏产生了Aspp1基因敲除小鼠。Aspp1(-/-)胚胎表现出皮下水肿和淋巴管系统紊乱。在Aspp1(-/-)胚胎中检测到淋巴管内皮细胞和孤立淋巴岛的形态学变化。通过向胚胎前肢皮下注射染料进行淋巴管造影显示，Aspp1(-/-)胚胎的淋巴管引流功能存在缺陷，收集淋巴管出现阻塞。有趣的是，Aspp1(-/-)成年小鼠解决了胚胎期出现的这些淋巴管功能缺陷，但Aspp1(-/-)成年小鼠的淋巴管造影显示收集淋巴管存在异常模式。由于据报道Aspp蛋白可增强p53的凋亡活性，我们询问p53缺乏是否也会影响淋巴管发育。对p53基因敲除或Aspp1；p53双基因敲除小鼠的分析表明，p53缺失不影响淋巴管。这些结果表明，Aspp1在小鼠发育过程中以不依赖p53的方式在淋巴管的初始组装和功能中起关键作用。在此我们报告Aspp1(-/-)小鼠的新型淋巴管表型；仅在胚胎期检测到的皮下水肿、淋巴管形成延迟以及收集淋巴管模式异常。
