Nlrp2, a Maternal Effect Gene Required for Early Embryonic Development in the Mouse

Abstract

Maternal effect genes encode proteins that are produced during oogenesis and play an essential role during early embryogenesis. Genetic ablation of such genes in oocytes can result in female subfertility or infertility. Here we report a newly identified maternal effect gene, Nlrp2, which plays a role in early embryogenesis in the mouse. Nlrp2 mRNAs and their proteins (∼118 KDa) are expressed in oocytes and granulosa cells during folliculogenesis. The transcripts show a striking decline in early preimplantation embryos before zygotic genome activation, but the proteins remain present through to the blastocyst stage. Immunogold electron microscopy revealed that the NLRP2 protein is located in the cytoplasm, nucleus and close to nuclear pores in the oocytes, as well as in the surrounding granulosa cells. Using RNA interference, we knocked down Nlrp2 transcription specifically in mouse germinal vesicle oocytes. The knockdown oocytes could progress through the metaphase of meiosis I and emit the first polar body. However, the development of parthenogenetic embryos derived from Nlrp2 knockdown oocytes mainly blocked at the 2-cell stage. The maternal depletion of Nlrp2 in zygotes led to early embryonic arrest. In addition, overexpression of Nlrp2 in zygotes appears to lead to normal development, but increases blastomere apoptosis in blastocysts. These results provide the first evidence that Nlrp2 is a member of the mammalian maternal effect genes and required for early embryonic development in the mouse.

Mutations in NLRP2 and NLRP5 cause female infertility characterised by early embryonic arrest

“…In our study, all probands with homozygous or compound heterozygous mutations in NRLP2 showed primary infertility and had histories of recurrent IVF/ICSI failure caused by early embryonic arrest. It has been shown in mice that severe reduction in the Nlrp2 protein level lead to lower blastocyst rates and that more embryos are arrested at the two-cell stage 20. The probands in families 1 and 2 who carried homozygous truncating mutations and compound heterozygous truncating and missense mutations in NLRP2 produced very few viable embryos.…”

Inflammasomes are neuroprotective targets for sex steroids

“…Recently, it became evident that a novel NLRP2 is expressed in human astrocytes and might have an important role in CNS inflammatory responses similar to the other known NLRPs, since it interacts with the P2 Â 7 receptor and the pannexin-1 channel [40]. Irrespectively of being involved in the inflammatory cascade, NLRP2 was recently discovered in mouse oocytes and granulosa cells during folliculogenesis and described as regulator of early embryogenesis [41]. Knockdown of NLRP2 led to an early embryonic arrest and suggest NLRP2 as a mammalian maternal effect gene required for normal embryonic development.…”

Birth defects and congenital health risks in children conceived through assisted reproduction technology (ART): a meeting report

“…There are no answers to such an overarching question but one glimpse into this quandary may be based in the integration between follicular and oocyte maturation [12]. Structural and physiological studies have now confirmed that a network of cellular interactions mediate critical aspects of oocyte metabolism that have a direct and immediate consequence of postfertilization development of the conceptus [10,13,14] (Fig. 1).…”