Truncated NLRC5 isoforms in human placenta: expression, regulation by miR-218-5p, and function in trophoblasts

A key event during placenta development is the differentiation of trophoblast progenitor cells into the invasive extravillous trophoblasts (EVTs) that migrate into the uterus. A subset of EVTs further acquire endothelial-like properties and differentiate into endovascular EVTs (enEVTs) to remodel the maternal spiral arteries. Proper EVT differentiation, migration/invasion, and spiral artery remodeling are critical for a healthy pregnancy. We recently reported that hsa-miR-218-5p promotes EVT/enEVT differentiation and spiral artery remodeling. In this study, we further investigated the mechanisms underlying the actions of miR-218-5p in human trophoblasts and identified NLRC5 as a target gene of miR-218-5p. Interestingly, we found that the human placenta expresses predominantly two transcript variants (v22 and v23) of the human NLRC5 gene, which encode two truncated protein isoforms 17 and 18 (i17 and i18). The expression of these isoforms declined during the active period of spiral artery remodeling. In vitro and ex vivo studies revealed that overexpression of v22 or v23 suppressed, while silencing of v22/23 enhanced, cell migration, invasion, endothelial-like network formation, and enEVT marker expression, as well as the EVT outgrowth of first trimester placental explants. Mechanistically, i17 and i18 regulated trophoblast activity by inhibiting NFκB. These findings suggest that NLRC5 isoforms are important regulators of EVT/enEVT differentiation and/or function, highlighting a novel miR-218-5p/NLRC5/NFκB signaling axis in placental development. ### Competing Interest Statement The authors have declared no competing interest.