ARHGEF18/p114RhoGEF Coordinates PKA/CREB Signaling and Actomyosin Remodeling to Promote Trophoblast Cell-Cell Fusion During Placenta Morphogenesis

Abstract

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 vitro and in vivo experiments identify that p114RhoGEF controls expression of AKAP12, a protein regulating protein kinase A (PKA) signaling, and is required for PKA-induced actomyosin remodeling, cAMP-responsive element binding protein (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 signaling, gene expression and cell-cell fusion.

Establishment and identification of cardiomyocyte arhGEF18 gene conditional knockout mice

“…These mice include global knockout and cKO mice. Reportedly, arhGEF18 global knockout mice have obvious embryo lethality, and the main cause of death may be placental development defects, so it is impossible to obtain homozygous newborn mice with global knockout of the arhGEF18 gene [25] . cKO is a site‐specific recombination technique using a system (the most common of which is the Cre‐LoxP system) on the basis of global knockout.…”

“…Reportedly, arhGEF18 global knockout mice have obvious embryo lethality, and the main cause of death may be placental development defects, so it is impossible to obtain homozygous newborn mice with global knockout of the arhGEF18 gene. [25] cKO is a site-specific recombination technique using a system (the most common of which is the Cre-LoxP system) on the basis of global knockout. This technique overcomes the defect of embryonic lethality caused by global knockout of some important genes and can more accurately reveal the specific role of target genes in specific cells or tissues.…”

Transcriptomic profiling of canine decidualization and effects of antigestagens on decidualized dog uterine stromal cells

“…Although still requiring confirmation, part of these effects might be associated with AKAP12 , which was modulated in all three sets of comparisons (contrasts). This scaffold protein regulates PKA and PKC activity by tethering the kinases to intracellular targets; it is associated with actin skeleton remodeling and cAMP-responsive element binding protein (CREB), regulating this way the cellular proliferation and activity 74 , 75 . Nevertheless, the role of this anchoring protein still requires further investigation in the dog.…”

ARHGEF18 participates in Endothelial Cell Mechano-sensitivity in Response to Flow

“…In the same line as p38 MAPK inhibition, the Y260A mutation does not trigger paracellular gaps, suggesting once more an additional role of ARHGEF18 independent of its nucleotide exchange activity. Interestingly, in mice, complete deletion of ARHGEF18 resulted in embryonic lethality 63 . ARHGEF18 null embryos showed reduced vasculature, increased hemorrhage and oedema, which is in line with our in vitro observation.…”