The pivotal roles of the NOD-like receptors with a PYD domain, NLRPs, in oocytes and early embryo development. Amoushahi M et al. (2019) Nucleotide-binding oligomerization domain (NOD)-like receptors with a pyrin domain (PYD), NLRPs, are pattern-recognition receptors, well recognized for their important roles in innate immunity and apoptosis. However, several NLRPs have received attention for their new, specialized roles as maternally contributed genes important in reproduction and embryo development. Several NLRPs have been shown to be specifically expressed in oocytes and preimplantation embryos. Interestingly, and in line with divergent functions, NLRP genes reveal a complex evolutionary divergence. The most pronounced difference is the human-specific NLRP7 gene, not identified in rodents. However, mouse models have been extensively used to study maternally contributed NLRPs. The NLRP2 and NLRP5 proteins are components of the subcortical maternal complex (SCMC), which was recently identified as essential for mouse preimplantation development. The SCMC integrates multiple proteins, including KHDC3L, NLRP5, TLE6, OOEP, NLRP2, and PADI6. The NLRP5 (also known as MATER) has been extensively studied. In humans, inactivating variants in specific NLRP genes in the mother are associated with distinct phenotypes in the offspring, such as biparental hydatidiform moles (BiHMs) and preterm birth. Maternal-effect recessive mutations in KHDC3L and NLRP5 (and NLRP7) are associated with reduced reproductive outcomes, BiHM, and broad multi-locus imprinting perturbations. The precise mechanisms of NLRPs are unknown, but research strongly indicates their pivotal roles in the establishment of genomic imprints and post-zygotic methylation maintenance, among other processes. Challenges for the future include translations of findings from the mouse model into human contexts and implementation in therapies and clinical fertility management.//////////////////
NCBI Summary:
This gene is a member of the nucleotide-binding and leucine-rich repeat receptor (NLR) family, and is predicted to contain an N-terminal pyrin effector domain (PYD), a centrally-located nucleotide-binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). Members of this gene family are thought to be important regulators of immune responses. This gene product interacts with components of the IkB kinase (IKK) complex, and can regulate both caspase-1 and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity. The pyrin domain is necessary and sufficient for suppression of NF-kB activity. An allelic variant (rs147585490) has been found that is incapable of blocking the transcriptional activity of NF-kB. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]
General function
, Epigenetic modifications
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Cellular localization
Cytoplasmic, Nuclear
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Ovarian function
Early embryo development
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Maternally expressed NLRP2 links the subcortical maternal complex (SCMC) to fertility, embryogenesis and epigenetic reprogramming. Mahadevan S et al. (2017) 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.//////////////////
Nlrp2, a maternal effect gene required for early embryonic development in the mouse. Peng H et al. 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.
Expression regulated by
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Ovarian localization
Oocyte, Granulosa
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Identification of oocyte-selective NLRP genes in rhesus macaque monkeys (Macaca mulatta). McDaniel P et al. Oocyte-selective genes control multiple aspects of female gamete development and preimplantation embryogenesis. Several key oocyte-selective factors have been identified in mice recently; however, these factors are not well documented in more advanced species such as nonhuman primates. One of such oocyte-selective factors is NLRP5 (NLR family, Pyrin domain containing 5), also known as Maternal Antigen That Embryos Require (MATER), which is required for preimplantation embryo development beyond the 2-cell stage in mice. Human NLRP family contains 14 members. We identified 14 NLRP gene homologues and examined their spatial and temporal expression in rhesus macaque monkeys (Macaca mulatta). While all 14 NLRP genes are detectable in the macaque gonad, eight of them (NLRP2, 4, 5, 8, 9, 11, 13, and 14) are specifically or preferentially expressed in the ovary. In situ hybridization elucidated a specific oocyte expression pattern of the eight NLRP genes within the ovary. During the oocyte-to-embryo transition, seven of these oocyte-selective NLRP transcripts (excluding NLPR2) are enriched in maturing oocytes and early preimplantation embryos but diminish upon embryo genome activation, indicating an exclusive maternal origin of these transcripts. Though functionally unknown, the spatial and temporal distribution of these oocyte-selective NLRP genes implies important roles of the NLRP family in oogenesis and early embryo development in nonhuman primates. Mol. Reprod. Dev. (c) 2008 Wiley-Liss, Inc.
Follicle stages
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Phenotypes
Mutations
3 mutations
Species: human
Mutation name: type: naturally occurring fertility: infertile - ovarian defect Comment: Germline mutation in NLRP2 (NALP2) in a familial imprinting disorder (Beckwith-Wiedemann Syndrome). Meyer E et al. (2009) Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.//////////////////
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: NLRP2 controls age-associated maternal fertility. Kuchmiy AA et al. (2016) Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are well-known for their key roles in the immune system. Ectopically expressed NLRP2 in immortalized cell lines assembles an inflammasome and inhibits activation of the proinflammatory transcription factor NF-κB, but the physiological roles of NLRP2 are unknown. Here, we show that Nlrp2-deficient mice were born with expected Mendelian ratios and that Nlrp2 was dispensable for innate and adaptive immunity. The observation that Nlrp2 was exclusively expressed in oocytes led us to explore the role of Nlrp2 in parthenogenetic activation of oocytes. Remarkably, unlike oocytes of young adult Nlrp2-deficient mice, activated oocytes of mature adult mice developed slower and largely failed to reach the blastocyst stage. In agreement, we noted strikingly declining reproductive rates in vivo with progressing age of female Nlrp2-deficient mice. This work identifies Nlrp2 as a critical regulator of oocyte quality and suggests that NLRP2 variants with reduced activity may contribute to maternal age-associated fertility loss in humans.//////////////////
Species: human
Mutation name: type: naturally occurring fertility: subfertile Comment: Maternal variants inNLRPand other maternal effect proteins are associated with multilocus imprinting disturbance in offspring. Begemann M et al. (2018) Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance. Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants inNLRP5have previously been found. We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, includingNLRP2,NLRP7andPADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss. The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.//////////////////