We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos. Further, UHRF1 is destabilized both in the cytoplasm and nucleus of Nlrp5 knockout murine FGOs. Since pathogenic variants of the SCMC components frequently cause multilocus imprinting disturbance and UHRF1 is essential for maintaining CpG methylation of imprinting control regions during preimplantation development, our results suggest possible pathogenesis behind the disease, which has been a long-standing mystery.
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Cryo-EM structure of the human subcortical maternal complex and the associated discovery of infertility-associated variants.
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Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
Article Synopsis
- The subcortical maternal complex (SCMC) is crucial for early mammalian embryonic development, and mutations in its key components (NLRP5, TLE6, OOEP) are linked to reproductive issues.
- Recent research has revealed the cryogenic electron microscopy structure of the human SCMC, highlighting the importance of the NLRP5 pyrin domain for maintaining the complex's stability.
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Variants in NLRP2 and ZFP36L2, non-core components of the human subcortical maternal complex, cause female infertility with embryonic development arrest.
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Department of Histology and Embryology, State Key Laboratory of Reproductive Medicine and Offspring Health, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China.
The subcortical maternal complex (SCMC), which is vital in oocyte maturation and embryogenesis, consists of core proteins (NLRP5, TLE6, OOEP), non-core proteins (PADI6, KHDC3L, NLRP2, NLRP7), and other unknown proteins that are encoded by maternal effect genes. Some variants of SCMC genes have been linked to female infertility characterized by embryonic development arrest. However, so far, the candidate non-core SCMC components associated with embryonic development need further exploration and the pathogenic variants that have been identified are still limited.
View Article and Find Full Text PDFThe maternal protein NLRP5 stabilizes UHRF1 in the cytoplasm: implication for the pathogenesis of multilocus imprinting disturbance.
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Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka 812-8582, Japan.
We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes.
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Genet Mol Biol
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Universidade Federal do Rio Grande do Sul (UFRGS), Programa de Pós-Graduação em Genética e Biologia Molecular, Porto Alegre, RS, Brazil.
The Subcortical Maternal Complex (SCMC) is composed of maternally encoded proteins required for the early stages of embryo development. Here we aimed to investigate the expression profile of the genes that encode the individual members of the SCMC in human reproductive failures. To accomplish that, we selected three datasets in the Gene Expression Omnibus repository for differential gene expression (DGE) analysis, comprising human endometrial and placental tissues of patients with recurrent implantation failure (RIF) or recurrent pregnancy loss (RPL).
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State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Nanjing, China.
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