Abstract
During human placentation, mononuclear cytotrophoblasts fuse to form multinucleated syncytia ensuring hormonal production and nutrient exchanges between the maternal and fetal circulation. Syncytial formation is essential for the maintenance of pregnancy and for fetal growth. The cAMP signaling pathway is the major route to trigger trophoblast fusion and its activation results in phosphorylation of specific intracellular target proteins, in transcription of fusogenic genes and assembly of macromolecular protein complexes constituting the fusogenic machinery at the plasma membrane. Specificity in cAMP signaling is ensured by generation of localized pools of cAMP controlled by cAMP phosphodiesterases (PDEs) and by discrete spatial and temporal activation of protein kinase A (PKA) in supramolecular signaling clusters inside the cell organized by A-kinase-anchoring proteins (AKAPs) and by organization of signal termination by protein phosphatases (PPs). Here we present original observations on the available components of the cAMP signaling pathway in the human placenta including PKA, PDE, and PP isoforms as well as AKAPs. We continue to discuss the current knowledge of the spatiotemporal regulation of cAMP signaling triggering trophoblast fusion.
Highlights
Cell fusion processes are essential for fertilization, fetal and placental development, skeletal muscle formation, bone homeostasis and appears to play a role in metastasis (Midgley et al, 1963; Zambonin Zallone et al, 1984; Wakelam, 1985; Oren-Suissa and Podbilewicz, 2007; Lu and Kang, 2009)
RIα is in the cytosol and decreases significantly during the cell fusion process and differentiation to STs while RIIα remains constant and relocates from the cytosol to the Golgi apparatus and to the plasma membrane (Keryer et al, 1998a,b)
We recently demonstrated that trophoblast fusion is regulated by ezrin, a known A-kinase-anchoring proteins (AKAPs), which binds to connexin-43 and delivers protein kinase A (PKA) in the vicinity gap junctions
Summary
Cell fusion processes are essential for fertilization, fetal and placental development, skeletal muscle formation, bone homeostasis and appears to play a role in metastasis (Midgley et al, 1963; Zambonin Zallone et al, 1984; Wakelam, 1985; Oren-Suissa and Podbilewicz, 2007; Lu and Kang, 2009). Throughout pregnancy CTs fuse to form a multinucleated syncytia on chorionic villi extending into the maternal placental blood circulation. Due to their capacity to differentiate into syncytia allowing essential placental exchange between mother and child necessary for fetal growth, the CT plays an essential role during human pregnancy. Numerous proteins have been reported to be implicated in cell fusion processes such as tight junction, adherens junction, and gap junction proteins (Coutifaris et al, 1991; Dahl et al, 1995; Mbalaviele et al, 1995; Ilvesaro et al, 2000; Frendo et al, 2003; Charrasse et al, 2007; Pidoux et al, 2010)
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