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Radcliffe Hospital, University of Oxfordhttps://www.ebi.ac.uk/ena/browser/view/PRJNA837955Mus musculusxref:PubMed:35906236Fetal growth restriction (FGR) affects 5-10% of pregnancies worldwide, and can have serious consequences for both mother and child. Both preventative and treatment strategies are currently largely lacking due to a poor understanding of the pathogenesis of FGR. There is strong genetic evidence for the involvement of KIR and HLA genes in FGR, however, the specific HLA and KIR risk alleles and their functional effects have been difficult to map due to linkage disequilibrium, maternal and paternal influence, and an inability to investigate pathological human pregnancies at critical early gestational stages. Here we demonstrate that the interaction between two defined genes, 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 humanised mouse model. We show that the initial KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and a modulation of uterine NK cell function. We delineate how this initial effect cascades to changes in transcriptional expression and intercellular communication in a myriad of cell types and pathways at the maternal-fetal interface. These findings reveal new mechanistic insight into the importance of specific KIR and HLA risk alleles in FGR, and provide new avenues of prevention and treatment to reduce disease burden and improve long-term health outcomes of the child. Overall design: We built a mouse single cell atlas of uterine NK cells at mid-gesttaion (gd9.5), using both full length scRNA-seq and 3’ droplet-based scRNA-Seq, from the three different mating groups: KIR x C*05 (FGR), WT x C*05 (control 1) and C*05/KIR x WT mice (control 2). In the full length scRNA-seq cohort, we had five replicates per mating group in the 3' droplet-based scRNA-Seq cohort, we had four replicates for WT x C*05 (control 1) and three replicates each for KIR x C*05 (FGR) and C*05/KIR x WT (control 2). We also analysed all cell types at the maternal-fetal interface at mid-gestation using droplet-based scRNA-seq from the three different mating groups, with three replicates per mating group.ENAless than 500 grams, foetal Growth retardation, Materials, 249 grams, FET GROWTH RET 750-999G, foetal SGA, Gene, Intrauterine Growth Retardation, Poor fetal growth state, Cistrons, FET GROWTH RETARD <500G, unspecified [weight], Intrauterine Growth Restriction, unspecified, Fetal Growth Retardation, 750-1, 999 grams, FET GROWTH RETARD WTNOS, FGR, FET GRWTH RET 1250-1499G, 1, 2, foetal small for gestational Age, Genetic Materials, NOS, intrauterine Growth restriction, IUGR, fetal SGA, Intrauterine, FET GRWTH RET 1000-1249G, Intrauterine growth retardation, Growth Retardation, FET GROWTH RET 500-749G, fetal small for gestational Age, Genetic, FET GRWTH RET 1500-1749G, Fetal growth retardation NOS (disorder), Fetal growth retardation (disorder), FET GROWTH RET 2500+G, Microsomic baby, fetal growth restriction, INSDC_feature:gene, IUGR - Intrauterine growth retardation, 500-1, foetal growth retardation, fetal growth retardation, 500+ grams, Fetal growth retardation NOS, Poor fetal growth, FGR - Fetal growth retardation, intrauterine Growth retardation, fetus small for gestational Age, 250-1, 500-749 grams, Material, foetus small for gestational Age, 750-999 grams, 000-1, 000-2, Fetal Growth Restriction, Microsomia, Foetal growth retardation, Cistron, FET GRWTH RET 2000-2499G, Fetal growth retardation, 749 grams, Genetic Material., 499 grams, FET GRWTH RET 1750-1999G, fetal Growth retardationless than 500 grams, foetal Growth retardation, Materials, 249 grams, FET GROWTH RET 750-999G, foetal SGA, Gene, Intrauterine Growth Retardation, Poor fetal growth state, Cistrons, FET GROWTH RETARD <500G, unspecified [weight], Intrauterine Growth Restriction, unspecified, Fetal Growth Retardation, 750-1, 999 grams, FET GROWTH RETARD WTNOS, FGR, FET GRWTH RET 1250-1499G, 1, 2, foetal small for gestational Age, Genetic Materials, NOS, intrauterine Growth restriction, IUGR, fetal SGA, Intrauterine, FET GRWTH RET 1000-1249G, Intrauterine growth retardation, Growth Retardation, FET GROWTH RET 500-749G, fetal small for gestational Age, Genetic, FET GRWTH RET 1500-1749G, Fetal growth retardation NOS (disorder), Fetal growth retardation (disorder), FET GROWTH RET 2500+G, Microsomic baby, fetal growth restriction, INSDC_feature:gene, IUGR - Intrauterine growth retardation, 500-1, foetal growth retardation, fetal growth retardation, 500+ grams, Fetal growth retardation NOS, Poor fetal growth, FGR - Fetal growth retardation, intrauterine Growth retardation, fetus small for gestational Age, 250-1, 500-749 grams, Material, foetus small for gestational Age, 750-999 grams, 000-1, 000-2, Fetal Growth Restriction, Microsomia, Foetal growth retardation, Cistron, FET GRWTH RET 2000-2499G, Fetal growth retardation, 749 grams, Genetic Material., 499 grams, FET GRWTH RET 1750-1999G, fetal Growth retardationfalseFetal growth restriction through parental and fetal immune gene variation and intercellular communications cascadeFetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade2025-09-242022-05-21PRJNA837955GSE2029831009035906236