Knockout animal models of HS-related genes and their associated hematopoietic phenotypes
| HS gene . | Species . | Type of knockout . | Significant/notable hematologic effect(s) . | References . |
|---|---|---|---|---|
| HSPGs | ||||
| Agrn | Mouse | Musk-L;Agrn−/− Whole body KO (with expression of Musk-L in skeletal tissue to rescue embryonic lethality) | Global absolute leukocyte reduction Reduction in monocytic lineage Severe anemia Disrupted erythroblastic islands | 65,66 |
| Srgn | Mouse | Whole body KO (viable) | Age-related enlargement of lymphoid tissue Age-related decrease in splenic CD4+ cells, peritoneal macrophages Increase in splenic naïve lymphocytes Mast cell secretory granule defects Cytotoxic T-cell defects Platelet, megakaryocyte, and neutrophil abnormalities | 67-70 |
| Gpc3 | Mouse | Whole body KO (perinatal lethality) | Poor HSC retention in BM Increased circulation of HSPCs Reduction in PMN, BM CD11b+, and GR-1+ cells | 71,72 |
| Sdc1 | Mouse | Whole body KO (prevention of surface expression of SDC1) | Slight increase in lineage-negative cells Impaired immune responses | 73 |
| Sdc2 | Zebrafish | Maternal zygotic deletion sdc2–/– | Immature/defective erythroid and neutrophil populations Poor response to infection | 74 |
| Sdc4 | Mouse | Whole body KO | Reduced B-cell number, migration, and deficient lymph-node germinal center formation in arthritis-induced model | 75 |
| Hspg2 (perlecan) | Drosophila | Trol (perlecan homolog) | Reduction in HSPC proliferation Precocious hematopoietic differentiation | 76 |
| Tgfbr3 | Mouse | Tgfbr3-LckCre (T cell) | Enhanced T-cell–dependent antibody response Increased Th1 T-cell differentiation | 77 |
| HS synthesis enzymes | ||||
| Ext1 | Mouse | Ext1–/– (embryonic lethal) Ext1+/− (viable) | Normal endogenous hematopoiesis Decreased HSPC engraftment upon transplant | 78 |
| Ext1 | Mouse | Ext1-CD19Cre (B cell) | Slightly increased Pro-B-cell population Reduced splenic B cells Reduced FGF2 binding/activation No change in antibody production/response | 79 |
| Extl3 | Zebrafish | Whole body KO | Defective thymopoiesis | 80 |
| HS-modifying enzymes | ||||
| Ndst1 | Mouse | NDST1-TekCre (Tie2) | No abnormal hematopoietic/blood parameters Slightly decreased bleeding time | 81 |
| Ndst1 | Mouse | NDST1-LckCre (T cell) | Altered T-cell activation and proliferation | 79 |
| Ndst2 | Mouse | Whole body KO | Impaired mast cell development/function | 82 |
| Ndst3 | Mouse | Whole body KO | Reduced circulating lymphocytes Reduced CD8+ T cells (spleen) | 83 |
| Hs2st1 | Mouse | Hs2st1-TekCre (Tie2), Hs2st1-LysMCre | No major hematopoietic phenotypes Enhanced neutrophil invasion and rolling | 84 |
| Hs6st1 | Mouse | Whole body KO | Scarce embryo–derived nucleated red blood cell in the placenta Mast cell granule defects | 85,86 |
| Hs6st2 | Mouse | Whole body KO | Mast cell granule defects | 85 |
| Glce | Mouse | GLCE–/– (fetal liver HSCs transplanted into Rag-2/IL2rg KO mice) | Impaired B-lineage development. Decreased plasma cells | 49 |
| Hpse | Mouse | Whole body KO | Slightly reduced total WBC Increased maturation of BM dendritic cells Impaired DC migration | 87,88 |
| HS gene . | Species . | Type of knockout . | Significant/notable hematologic effect(s) . | References . |
|---|---|---|---|---|
| HSPGs | ||||
| Agrn | Mouse | Musk-L;Agrn−/− Whole body KO (with expression of Musk-L in skeletal tissue to rescue embryonic lethality) | Global absolute leukocyte reduction Reduction in monocytic lineage Severe anemia Disrupted erythroblastic islands | 65,66 |
| Srgn | Mouse | Whole body KO (viable) | Age-related enlargement of lymphoid tissue Age-related decrease in splenic CD4+ cells, peritoneal macrophages Increase in splenic naïve lymphocytes Mast cell secretory granule defects Cytotoxic T-cell defects Platelet, megakaryocyte, and neutrophil abnormalities | 67-70 |
| Gpc3 | Mouse | Whole body KO (perinatal lethality) | Poor HSC retention in BM Increased circulation of HSPCs Reduction in PMN, BM CD11b+, and GR-1+ cells | 71,72 |
| Sdc1 | Mouse | Whole body KO (prevention of surface expression of SDC1) | Slight increase in lineage-negative cells Impaired immune responses | 73 |
| Sdc2 | Zebrafish | Maternal zygotic deletion sdc2–/– | Immature/defective erythroid and neutrophil populations Poor response to infection | 74 |
| Sdc4 | Mouse | Whole body KO | Reduced B-cell number, migration, and deficient lymph-node germinal center formation in arthritis-induced model | 75 |
| Hspg2 (perlecan) | Drosophila | Trol (perlecan homolog) | Reduction in HSPC proliferation Precocious hematopoietic differentiation | 76 |
| Tgfbr3 | Mouse | Tgfbr3-LckCre (T cell) | Enhanced T-cell–dependent antibody response Increased Th1 T-cell differentiation | 77 |
| HS synthesis enzymes | ||||
| Ext1 | Mouse | Ext1–/– (embryonic lethal) Ext1+/− (viable) | Normal endogenous hematopoiesis Decreased HSPC engraftment upon transplant | 78 |
| Ext1 | Mouse | Ext1-CD19Cre (B cell) | Slightly increased Pro-B-cell population Reduced splenic B cells Reduced FGF2 binding/activation No change in antibody production/response | 79 |
| Extl3 | Zebrafish | Whole body KO | Defective thymopoiesis | 80 |
| HS-modifying enzymes | ||||
| Ndst1 | Mouse | NDST1-TekCre (Tie2) | No abnormal hematopoietic/blood parameters Slightly decreased bleeding time | 81 |
| Ndst1 | Mouse | NDST1-LckCre (T cell) | Altered T-cell activation and proliferation | 79 |
| Ndst2 | Mouse | Whole body KO | Impaired mast cell development/function | 82 |
| Ndst3 | Mouse | Whole body KO | Reduced circulating lymphocytes Reduced CD8+ T cells (spleen) | 83 |
| Hs2st1 | Mouse | Hs2st1-TekCre (Tie2), Hs2st1-LysMCre | No major hematopoietic phenotypes Enhanced neutrophil invasion and rolling | 84 |
| Hs6st1 | Mouse | Whole body KO | Scarce embryo–derived nucleated red blood cell in the placenta Mast cell granule defects | 85,86 |
| Hs6st2 | Mouse | Whole body KO | Mast cell granule defects | 85 |
| Glce | Mouse | GLCE–/– (fetal liver HSCs transplanted into Rag-2/IL2rg KO mice) | Impaired B-lineage development. Decreased plasma cells | 49 |
| Hpse | Mouse | Whole body KO | Slightly reduced total WBC Increased maturation of BM dendritic cells Impaired DC migration | 87,88 |
Summary of current animal models with genetic perturbations of HSPGs, HS synthesis enzymes, or HS-modifying enzymes and their hematopoietic phenotypes.
KO, knockout.