Nodal Signals through Activin Receptor-Like Kinase 7 to Inhibit Trophoblast Migration and Invasion

Abstract

Trophoblast cell invasion into the uterus is an essential process for successful pregnancy, and shallow invasion of trophoblasts into the maternal decidua is linked to preeclampsia. We have reported that Nodal, a member of the transforming growth factor-␤ superfamily, acts through activin receptor-like kinase 7 (ALK7) to inhibit trophoblast proliferation and to induce apoptosis. In this study, we examined the spatial and temporal expression patterns of Nodal and ALK7 in human placenta from normal and preeclamptic pregnancies and investigated whether Nodal regulated trophoblast migration and invasion. Nodal and ALK7 were detected in villous and extravillous trophoblast cell populations in early gestation, and their levels were strongly up-regulated in preeclamptic placenta. Overexpression of Nodal or constitutively active ALK7 decreased cell migration and invasion, whereas knockdown of Nodal and ALK7 had the opposite effects. In placental explant culture, treatment with Nodal inhibited trophoblast outgrowth, whereas Nodal small-interfering RNA strongly induced the expansion of explants and the migration of extravillous trophoblast cells. Nodal stimulated the secretion of tissue inhibitor of metalloproteinase-1 and inhibited matrix metalloproteinase (MMP)-2 and MMP-9 activity. These findings suggest that the Nodal/ALK7 pathway plays important roles in human placentation and that its abnormal signaling may contribute to the development of preeclampsia.

Maternal Nodal inversely affects NODAL and STOX1 expression in the fetal placenta

“…For example, it has been shown that Nodal upregulation induces apoptosis and inhibits proliferation of a trophoblast cell line (HTR8/SVNeo) leading to reduced invasion (Munir et al, 2004). More importantly, Nodal has also been found to be increased in placentas from pre-eclamptic patients (Nadeem et al, 2011). In this study we furthermore observed that reduced Nodal activity in the maternal decidua induced Activin-A transcription leading to increased levels of Activin-A excretion.…”

Activin/Nodal Signaling Switches the Terminal Fate of Human Embryonic Stem Cell-derived Trophoblasts

“…Therefore, hESC-derived trophoblasts are capable of forming iCTBs or STBs when exposed to relevant extracellular cues, similar to human placental trophoblasts. Other functional properties of first and third trimester trophoblasts and mouse trophoblasts have been reported, such as their differential response to nodal and activin treatment (58,(73)(74)(75)(76). These should also be tested in hESC-derived trophoblasts, although these studies are beyond the scope of this work.…”

Nodal signalling and asymmetry of the nervous system

“…It is known, for example, that Nodal signalling can maintain pluripotency and prevent differentiation to neuroectoderm in human embryonic stem cells (hESC) and mouse epiblastderived stems cells (mEpiSC) [32] while it is necessary for endoderm differentiation in pluripotent cells and the mouse gastrula embryo [3,33]. Similarly, Nodal can inhibit cell migration, invasion and proliferation in human trophoblasts [34,35] while it promotes the opposite in human glioma and breast cancer cells [36,37]. Such divergent mechanisms create the necessity of developing a conceptual framework to help recognize L-R patterns and assess the phenomenon in a meaningful manner.…”