Loss of the Maternal Effect Gene Nlrp2 Impairs Embryonic and Extra-Embryonic Development, Unveiling a Novel Cause of Congenital Anomalies

Maternal effect genes (MEGs) are expressed in the oocyte and early mammalian preimplantation embryo. Impaired MEG function can impact offspring development and health. We investigated the consequences of postimplantation embryonic and extra-embryonic development in mice with maternal loss-of-function of Nlrp2, an MEG that encodes a protein of the subcortical maternal complex (SCMC). We employed three mating schemes, wildtype (WT) x WT, maternal Nlrp2-knock-out (KO) x WT, and WT x paternal Nlrp2-KO, to study the embryonic and extraembryonic phenotypes at embryonic day 11.5. Concepti of maternal Nlrp2-KO matings have striking abnormalities, including aberrant yolk sac vasculature, lower embryo to yolk sac area ratios, increased embryo resorption, and embryos with variably severe craniofacial abnormalities, and congenital heart defects. The placentas have significant morphological abnormalities, particularly in the junctional zone and labyrinth layers. This indicates that Nlrp2 is important for trophoblast development and placental architecture, supported by significantly altered gene expression profiles in the placentas of pregnant Nlrp2-KO mice. Taken together, these findings highlight the importance of maternal Nlrp2 for embryonic and placental development, and for the first time confirm that inactivating maternal effect mutations can cause disrupted placental development along with congenital cardiac and other anomalies. In conclusion, maternal loss of Nlrp2 profoundly impacts mouse embryonic and extra-embryonic development, highlighting a new role of MEGs. These findings pave the way for future research into genetic mechanisms underlying congenital anomalies and developmental disorders.