Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta
Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta
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DOI：
10.1016/s0960-9822(99)80164-x
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发表时间：
1999-04-08
期刊：
影响因子：
9.2
通讯作者：
Charron, J
中科院分区：
文献类型：
--
作者：
Giroux, S;Tremblay, M;Charron, J
Mek 是一种双特异性激酶，在激动剂与受体结合后激活细胞外信号调节 (Erk) 丝裂原激活蛋白 (MAP) 激酶。 Erk MAP 激酶级联参与许多生物体的细胞命运决定。在哺乳动物中，该途径被认为调节细胞生长和分化。遗传学研究表明，虽然秀丽隐杆线虫、果蝇和爪蟾中存在单个 mek 基因，但哺乳动物级联中存在两个 mek 同源物 Mek1 和 Mek2。在本研究中，我们描述了一种突变小鼠系，其中 mek1 基因已被插入诱变破坏。无效突变是隐性致死的，因为纯合突变胚胎在妊娠 10.5 天时死亡。组织病理学分析显示胎盘血管化减少是由于迷路区域血管内皮细胞显着减少所致。未能建立功能性胎盘可能解释了 mek1(-/-) 胚胎的死亡。细胞迁移实验表明，尽管Mek2蛋白和Erk激活水平正常，但纤连蛋白不能诱导mek1(-/-)成纤维细胞迁移。 Mek1 在突变小鼠胚胎成纤维细胞 (MEF) 中的重新表达恢复了它们的迁移能力。我们的研究结果提供了遗传证据，证实了 Mek1 在信号转导中发挥的独特作用。他们还表明，mek1 功能是对血管生成信号的正常反应所必需的，血管生成信号可能促进胎盘迷路区域的血管化。
Mek is a dual-specificity kinase that activates the extracellular-signal-regulated (Erk) mitogen-activated protein (MAP) kinases upon agonist binding to receptors. The Erk MAP kinase cascade is involved in cell-fate determination in many organisms. In mammals, this pathway is proposed to regulate cell growth and differentiation. Genetic studies have shown that although a single mek gene is present in Caenorhabditis elegans, Drosophila and Xenopus, two mek homologs, Mek1 and Mek2, are present in the mammalian cascade. In the present study, we describe a mutant mouse line in which the mek1 gene has been disrupted by insertional mutagenesis. The null mutation was recessive lethal, as the homozygous mutant embryos died at 10.5 days of gestation. Histopathological analyses revealed a reduction in vascularization of the placenta that was due to a marked decrease of vascular endothelial cells in the labyrinthine region. The failure to establish a functional placenta probably explains the death of the mek1(-/-) embryos. Cell-migration assays indicated that mek1(-/-) fibroblasts could not be induced to migrate by fibronectin, although the levels of Mek2 protein and Erk activation were normal. Re-expression of Mek1 in the mutant mouse embryonic fibroblasts (MEFs) restored their ability to migrate. Our findings provide genetic evidence that establishes the unique role played by Mek1 in signal transduction, They also suggest that mek1 function is required for normal response to angiogenic signals that might promote vascularization of the labyrinthine region of the placenta.