Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells
Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells
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DOI：
10.1091/mbc.e07-12-1215
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发表时间：
2008-06-01
影响因子：
3.3
通讯作者：
Tsukita, Sachiko
中科院分区：
文献类型：
--
作者：
Katsuno, Tatsuya;Umeda, Kazuaki;Tsukita, Sachiko
Zonula occludens(ZO)-1/2/3是TJ-Maguk家族中与紧密连接相关的膜相关鸟苷晚期蛋白家族的成员。为了研究ZO-1(由Tjp1编码)在体内的作用，通过基因打靶的方法建立了ZO-1基因敲除(Tjp1(-/-))小鼠。虽然杂合子小鼠表现出正常的发育和生育能力，但从E8.5开始，Tjp1(-/-)胚胎的生长和发育明显延迟，超过E11.5的Tjp1(-/-)胚胎没有观察到存活的胚胎。在胚胎第9.5天，Tjp1(-/-)胚胎在脊索、神经管区和尿囊区出现大量的细胞凋亡。在卵黄囊中，ZO-1缺乏导致血管发育缺陷，维管树的形成受损，并伴有绒毛尿囊融合缺陷。对E8.5的野生型胚胎进行ZO-1/2/3免疫组织化学染色显示，ZO-1/2在几乎所有胚胎细胞中都有表达，呈紧密连接定位模式，无论有无ZO-3，ZO-1/2仅局限于上皮细胞。ZO-1缺乏抑制了ZO-1的表达，但不影响ZO-2/3的表达。在Tjp1(-/-)卵黄囊胚外中胚层中，ZO-1占优势，ZO-2/3不表达。因此，ZO-1缺乏导致中胚层没有ZO-1/2/3，与内皮连接黏附分子的错误定位有关。结果，尽管内皮细胞的分化似乎正常，但Tjp1(-/-)卵黄囊中的血管生成存在缺陷。综上所述，ZO-1在胚胎和胚胎外区域的细胞重塑和组织组织中可能具有重要的功能，从而在胚胎发育中发挥重要作用。
Zonula occludens (ZO)-1/2/3 are the members of the TJ-MAGUK family of membrane-associated guanylate kinases associated with tight junctions. To investigate the role of ZO-1 (encoded by Tjp1) in vivo, ZO-1 knockout (Tjp1(-/-)) mice were generated by gene targeting. Although heterozygous mice showed normal development and fertility, delayed growth and development were evident from E8.5 onward in Tjp1(-/-) embryos, and no viable Tjp1(-/-) embryos were observed beyond E11.5. Tjp1(-/-) embryos exhibited massive apoptosis in the notochord, neural tube area, and allantois at embryonic day (E) 9.5. In the yolk sac, the ZO-1 deficiency induced defects in vascular development, with impaired formation of vascular trees, along with defective chorioallantoic fusion. Immunostaining of wild-type embryos at E8.5 for ZO-1/2/3 revealed that ZO-1/2 were expressed in almost all embryonic cells, showing tight junction-localizing patterns, with or without ZO-3, which was confined to the epithelial cells. ZO-1 deficiency depleted ZO-1-expression without influence on ZO-2/3 expression. In Tjp1(-/-) yolk sac extraembryonic mesoderm, ZO-1 was dominant without ZO-2/3 expression. Thus, ZO-1 deficiency resulted in mesoderms with no ZO-1/2/3, associated with mislocalization of endothelial junctional adhesion molecules. As a result, angiogenesis was defected in Tjp1(-/-) yolk sac, although differentiation of endothelial cells seemed to be normal. In conclusion, ZO-1 may be functionally important for cell remodeling and tissue organization in both the embryonic and extraembryonic regions, thus playing an essential role in embryonic development.