ARHGEF18/p114RhoGEF coordinates PKA/CREB signaling and actomyosin remodeling to drive trophoblast cell-cell fusion during placenta morphogenesis
ARHGEF18/p114RhoGEF coordinates PKA/CREB signaling and actomyosin remodeling to drive trophoblast cell-cell fusion during placenta morphogenesis
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ARHGEF18/p114RhoGEF 协调 PKA/CREB 信号传导和肌动球蛋白重塑，在胎盘形态发生过程中驱动滋养层细胞-细胞融合
DOI：
10.1101/2020.07.12.199141
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Beal R
中科院分区：
文献类型：
--
作者：
Beal R
细胞-细胞粘附、肌动球蛋白动力学和基因表达的协调对于组织和器官发育的形态发生过程至关重要。Rho GTP酶是细胞骨架和粘附的主要调节剂。它们被鸟嘌呤核苷酸交换因子以空间和时间控制的方式激活。然而，在复杂的发育过程中，这些Rho GT3激活剂的作用仍然知之甚少。ARHGEF 18/p114 RhoGEF是一种紧密连接相关的RhoA激活剂，与肌球蛋白II形成复合物，并调节肌动球蛋白收缩性。在这里，我们表明，p114 RhoGEF/ARHGEF 18是必需的小鼠合胞体滋养层分化和胎盘development.In体外和体内实验确定，p114 RhoGEF控制AKAP 12，蛋白调节PKA信号的表达，并需要PKA诱导的肌动球蛋白重塑，CREB驱动的基因表达的蛋白质所需的滋养层分化，因此，滋养层细胞-细胞融合。因此，我们的数据表明，p114 RhoGEF链接肌动球蛋白动力学和细胞连接PKA/CREB信号，基因表达和细胞融合。
Coordination of cell-cell adhesion, actomyosin dynamics and gene expression is crucial for morphogenetic processes underlying tissue and organ development. Rho GTPases are main regulators of the cytoskeleton and adhesion. They are activated by guanine nucleotide exchange factors in a spatially and temporally controlled manner. However, the roles of these Rho GTPase activators during complex developmental processes are still poorly understood. ARHGEF18/p114RhoGEF is a tight junction-associated RhoA activator that forms complexes with myosin II, and regulates actomyosin contractility. Here we show that p114RhoGEF/ ARHGEF18 is required for mouse syncytiotrophoblast differentiation and placenta development.In vitroandin vivoexperiments identify that p114RhoGEF controls expression of AKAP12, a protein regulating PKA signalling, and is required for PKA-induced actomyosin remodelling, CREB-driven gene expression of proteins required for trophoblast differentiation, and, hence, trophoblast cell-cell fusion. Our data thus indicate that p114RhoGEF links actomyosin dynamics and cell-cell junctions to PKA/CREB signalling, gene expression and cell-cell fusion.