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Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

Author

Listed:
  • Gurman Kaur

    (University of Oxford
    Broad Institute of MIT and Harvard)

  • Caroline B. M. Porter

    (Broad Institute of MIT and Harvard)

  • Orr Ashenberg

    (Broad Institute of MIT and Harvard)

  • Jack Lee

    (King’s College London)

  • Samantha J. Riesenfeld

    (Broad Institute of MIT and Harvard
    University of Chicago
    University of Chicago)

  • Matan Hofree

    (Broad Institute of MIT and Harvard)

  • Maria Aggelakopoulou

    (University of Oxford)

  • Ayshwarya Subramanian

    (Broad Institute of MIT and Harvard)

  • Subita Balaram Kuttikkatte

    (University of Oxford)

  • Kathrine E. Attfield

    (University of Oxford)

  • Christiane A. E. Desel

    (University of Oxford
    University Hospital Magdeburg)

  • Jessica L. Davies

    (University of Oxford)

  • Hayley G. Evans

    (University of Oxford)

  • Inbal Avraham-Davidi

    (Broad Institute of MIT and Harvard)

  • Lan T. Nguyen

    (Broad Institute of MIT and Harvard)

  • Danielle A. Dionne

    (Broad Institute of MIT and Harvard)

  • Anna E. Neumann

    (Broad Institute of MIT and Harvard)

  • Lise Torp Jensen

    (Aarhus University Hospital)

  • Thomas R. Barber

    (University of Oxford)

  • Elizabeth Soilleux

    (University of Cambridge)

  • Mary Carrington

    (National Cancer Institute
    Ragon Institute of MGH, MIT, and Harvard)

  • Gil McVean

    (University of Oxford)

  • Orit Rozenblatt-Rosen

    (Broad Institute of MIT and Harvard
    Genentech, 1 DNA Way)

  • Aviv Regev

    (Broad Institute of MIT and Harvard
    Department of Biology
    Howard Hughes Medical Institute
    Genentech, 1 DNA Way)

  • Lars Fugger

    (University of Oxford
    University of Oxford
    Aarhus University Hospital)

Abstract

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

Suggested Citation

  • Gurman Kaur & Caroline B. M. Porter & Orr Ashenberg & Jack Lee & Samantha J. Riesenfeld & Matan Hofree & Maria Aggelakopoulou & Ayshwarya Subramanian & Subita Balaram Kuttikkatte & Kathrine E. Attfiel, 2022. "Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32171-w
    DOI: 10.1038/s41467-022-32171-w
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    References listed on IDEAS

    as
    1. Momoko Horikoshi & Robin N. Beaumont & Felix R. Day & Nicole M. Warrington & Marjolein N. Kooijman & Juan Fernandez-Tajes & Bjarke Feenstra & Natalie R. van Zuydam & Kyle J. Gaulton & Niels Grarup & J, 2016. "Genome-wide associations for birth weight and correlations with adult disease," Nature, Nature, vol. 538(7624), pages 248-252, October.
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