DELETION OF BETA-1 INTEGRINS IN MICE RESULTS IN INNER CELL MASS FAILURE AND PERIIMPLANTATION LETHALITY
DELETION OF BETA-1 INTEGRINS IN MICE RESULTS IN INNER CELL MASS FAILURE AND PERIIMPLANTATION LETHALITY
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DOI：
10.1101/gad.9.15.1883
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发表时间：
1995-08-01
影响因子：
10.5
通讯作者：
DAMSKY, CH
中科院分区：
文献类型：
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作者：
STEPHENS, LE;SUTHERLAND, AE;DAMSKY, CH
细胞外基质受体的整合素受体是培养细胞中细胞粘附、分化和迁移的重要效应物，并且被认为是发育过程中这些过程的关键效应物。为了确定 β1 整合素何时在胚胎发育过程中变得至关重要，我们培育了对 β1 整合素亚基基因进行有针对性破坏的突变小鼠。杂合突变小鼠是正常的。 β1 整合素表达的纯合性缺失在植入后早期发育过程中是致命的。缺乏β1整合素的纯合胚胎形成外观正常的囊胚，并在E4.5开始植入。然而，原位E4.5 beta 1无效胚胎的囊胚腔塌陷，并且滋养层穿透子宫上皮，但没有观察到蜕膜的广泛侵入。在内细胞团区检测到层粘连蛋白阳性内胚层细胞，但内胚层形态发生和迁移有缺陷。到 E5.5，β1 缺失胚胎已广泛退化。体外分析表明，β1缺失的围植入期胚胎的滋养层功能基本正常，包括组织特异性标记物的表达，以及在纤连蛋白和玻连蛋白包被的基质上生长，但在层粘连蛋白包被的基质上则不然。相反，β1无效囊胚生长物的内细胞团区域以及从β1无效囊胚分离的内细胞团表现出高度迟缓的生长和有缺陷的胚外内胚层形态发生和迁移。这些数据表明β1整联蛋白是内细胞团正常形态发生所必需的，并且是内细胞团细胞生长和存活的重要介质。内细胞团失败后，β 1 缺失胚胎中滋养层持续发育失败可能是由于滋养层发育后期对 β 1 整合素的内在需求，或者是由于缺乏来自 β 1 缺失内细胞团的营养信号。
Integrin receptors for extracellular matrix receptors are important effecters of cell adhesion, differentiation, and migration in cultured cells and are believed to be critical effecters of these processes during development. To determine when beta 1 integrins become critical during embryonic development, we generated mutant mice with a targeted disruption of the beta 1 integrin subunit gene. Heterozygous mutant mice were normal. Homozygous loss of beta 1 integrin expression was lethal during early postimplantation development. Homozygous embryos lacking beta 1 integrins formed normal-looking blastocysts and initiated implantation at E4.5. However, the E4.5 beta 1-null embryos in situ had collapsed blastocoeles, and whereas the trophoblast penetrated the uterine epithelium, extensive invasion of the decidua was not observed. Laminin-positive endoderm cells were detected in the inner cell mass area, but endoderm morphogenesis and migration were defective. By E5.5 beta 1-null embryos had degenerated extensively. In vitro analysis showed that trophoblast function in beta 1-null peri-implantation embryos was largely normal, including expression of tissue-specific markers, and outgrowth on fibronectin- and vitronectin-coated, although not on laminin-coated substrates. In contrast, the inner cell mass region of beta 1-null blastocyst outgrowths, and inner cell masses isolated from beta 1-null blastocysts, showed highly retarded growth and defective extraembryonic endoderm morphogenesis and migration. These data suggest that beta 1 integrins are required for normal morphogenesis of the inner cell mass and are essential mediators of growth and survival of cells of the inner cell mass. Failure of continued trophoblast development in beta 1-null embryos after inner cell mass failure could be attributable to either an intrinsic requirement for beta 1 integrins for later stages of trophoblast development, or to the lack of trophic signals from the beta 1-null inner cell mass.