Abstract
Mammalian parental genomes contribute differently to early embryonic development. Before activation of the zygotic genome, the maternal genome provides all transcripts and proteins required for the transition from a highly specialized oocyte to a pluripotent embryo. Depletion of these maternally-encoded transcripts frequently results in failure of preimplantation embryonic development, but their functions in this process are incompletely understood. We found that female mice lacking NLRP2 are subfertile because of early embryonic loss and the production of fewer offspring that have a wide array of developmental phenotypes and abnormal DNA methylation at imprinted loci. By demonstrating that NLRP2 is a member of the subcortical maternal complex (SCMC), an essential cytoplasmic complex in oocytes and preimplantation embryos with poorly understood function, we identified imprinted postzygotic DNA methylation maintenance, likely by directing subcellular localization of proteins involved in this process, such as DNMT1, as a new crucial role of the SCMC for mammalian reproduction.
Highlights
Infertility and pregnancy loss are common forms of reproductive failure, with primary and secondary infertility affecting 1.9% and 10.5% of women respectively[1]
Maternal mutations in NLRP2, which is highly homologous to NLRP7 and immediately adjacent to it on chromosome 19, have been described in one family to result in an multilocus imprinting disturbance (MLID) that presents as recurrent Beckwith-Wiedemann Syndrome due to loss of DNA methylation at the imprinted KvDMR1 CpG island (CGI), associated with loss of methylation at the differentially methylated regions (DMRs) of at least one other imprinted locus, PEG122
Β-Gal staining was only visible in the ovaries of Nlrp2tm1a/+ and Nlrp2tm1a/tm1a females where it is restricted to oocytes (Fig. 1C). qRT-PCR amplification of expressed Nlrp[2] from whole ovaries of 3-week-old mice revealed its complete absence in Nlrp2tm1a/tm1a mice when normalized to Gapdh (P < 0.0001, Fig. 1D, left panel) or to levels of a germ cell specific gene, Mouse Vasa homolog (Mvh) (P = 0.0021, Fig. 1D, right panel)
Summary
Infertility and pregnancy loss are common forms of reproductive failure, with primary and secondary infertility affecting 1.9% and 10.5% of women respectively[1]. Women with loss of function mutations in the gene encoding NLRP5 (NLR Family, Pyrin Domain-Containing 5), a member of a subclass of NLR family of proteins that is highly expressed in germ cells and preimplantation embryos[19,20], can have recurrent pregnancy loss as well as liveborn children who have abnormal DNA methylation at multiple imprinted loci, indicative of multilocus imprinting disturbance (MLID), and a wide range of clinical phenotypes[21] These combined observations point to a role for the SCMC in postzygotic maintenance of DNA methylation at imprinted genes[17,21]. These results define a new member of the SCMC complex and identify postzygotic maintenance of DNA methylation at imprinted genes, conferred in part by ensuring appropriate localization of DNMT1, as a function of the SCMC that is critical for preimplantation development and successful pregnancy
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