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Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming.

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.

SUBMITTER: Mahadevan S

PROVIDER: S-EPMC5357799 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming.

Mahadevan Sangeetha S Sathappan Varsha V Utama Budi B Lorenzo Isabel I Kaskar Khalied K Van den Veyver Ignatia B IB

Scientific reports 20170320

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 su ...[more]

PMID: 28317850

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Project description:Study questionWhat are the genetic factors that increase the risk of aneuploid egg production?Summary answerA non-synonymous variant rs2303720 within centrosomal protein 120 (CEP120) disrupts female meiosis in vitro in mouse.What is known alreadyThe production of aneuploid eggs, with an advanced maternal age as an established contributing factor, is the major cause of IVF failure, early miscarriage and developmental anomalies. The identity of maternal genetic variants contributing to egg aneuploidy irrespective of age is missing.Study design, size, durationPatients undergoing fertility treatment (n = 166) were deidentified and selected for whole-exome sequencing.Participants/materials, setting, methodsPatients self-identified their ethnic groups and their ages ranged from 22 to 49 years old. The study was performed using genomes from White, non-Hispanic patients divided into controls (97) and cases (69) according to the number of aneuploid blastocysts derived during each IVF procedure. Following a gene prioritization strategy, a mouse oocyte system was used to validate the functional significance of the discovered associated genetic variants.Main results and the role of chancePatients producing a high proportion of aneuploid blastocysts (considered aneuploid if they missed any of the 40 chromatids or had extra copies) were found to carry a higher mutational burden in genes functioning in cytoskeleton and microtubule pathways. Validation of the functional significance of a non-synonymous variant rs2303720 within Cep120 on mouse oocyte meiotic maturation revealed that ectopic expression of CEP120:p.Arg947His caused decreased spindle microtubule nucleation efficiency and increased incidence of aneuploidy.Limitations, reasons for cautionFunctional validation was performed using the mouse oocyte system. Because spindle building pathways differ between mouse and human oocytes, the defects we observed upon ectopic expression of the Cep120 variant may alter mouse oocyte meiosis differently than human oocyte meiosis. Further studies using knock-in 'humanized' mouse models and in human oocytes will be needed to translate our findings to human system. Possible functional differences of the variant between ethnic groups also need to be investigated.Wider implications of the findingsVariants in centrosomal genes appear to be important contributors to the risk of maternal aneuploidy. Functional validation of these variants will eventually allow prescreening to select patients that have better chances to benefit from preimplantation genetic testing.Study funding/competing interest(s)This study was funded through R01-HD091331 to K.S. and J.X. and EMD Serono Grant for Fertility Innovation to N.R.T. N.R.T. is a shareholder and an employee of Genomic Prediction.Trial registration numberN/A.

Dataset Information

Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming.

Publications

Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming.

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