The schematic diagram shows the signaling cascade for syncytiotrophoblast (STB) induction in hTSCs. In brief, STB differentiation is modeled in 2D culture with FRSK (I) or organoid culture to mimicin vivo differentiation (II) via GPCR(s) activation, which is purported to include hCG binding its receptor, LHCGR. Stimulation of adenylyl cyclase (AC) induces STB differentiation by converting ATP to cAMP to activate protein kinase A (PKA), resulting in MAPK cascade activation, which culminates in CREB and ATF-1 TF activation, via phosphorylation, and binding to cAMP-responsive elements (CREs red DNA motif). DNA methylation of CRE motifs blocks CREB:ATF-1 binding, and loss of DNMT expression is hypothesized to lead to unmethylated CRE motifs. Methylation-insensitive TFs (blue) activated by MAPKs can bind to their target motifs.
