ADAR1 knockout models and the impact on hematopoietic cell development
| Cell type . | Genetic model . | Range . | Outcomes . | References . |
|---|---|---|---|---|
| Embryonic hematopoiesis | Adar1+/− | Genome wide | Died before E14 with defects in the hematopoietic system | 81 |
| Adar1−/− | Genome wide | Died around E12 with liver integration | 82 | |
| Embryonic HSPCs | Mx1-Cre; Adarf/− | Hematopoietic system | Result in low engraftment and elicit a global IFN response | 84 |
| Adult HSPCs | SCL-Cre-ER; Adarf/- | HSCs | Reduced LT-HSC (LKS+CD34lo) number and elevated IFN signaling | 84 |
| Adult HSPCs | MSCV-Cre; Adar1f/f ER-Cre; Adar1f/f | HSPCs | Low engraftment but increased frequency of SLAM HSCs (Lin–CD48–CD150+) Increase apoptosis of differentiating HPCs (Lin–c-Kit+Sca-1–) | 85 |
| Erythropoiesis | Epor-Cre; Adar1Δ/− Epor-Cre; Adar1Δ/E861A | From Pre-Meg-E population downward | Died in utero at E14.5 Macrocytic anemia and splenomegaly | 86 |
| Myeloid cells | LysM-Cre; Adar1f/f | Myelomonocytic cells | Exhibit significantly reduced AM numbers, giant AM, and significant alveolar lipid accumulation | 86,87 |
| Macrophages | Lyz2(LysM)-Cre; Adarf/f | Macrophages | Establish an antitumor microenvironment | 88 |
| DCs | Cd11c-Cre; Adar1f/f | DCs | Fail to expand normal numbers of CD103+ DC Increase inflammatory cDC2-like cells and promote early resistance against SARS-CoV-2 infection | 87,89 |
| T cells | Lck-Cre; Adar1f/f | Early T-cell stage (from DN stage onward) | Reduce TCRβ expression but increase expression of type I ISGs in thymocytes | 90,91 |
| T cells | Cd4-Cre; Adar1f/f | Late T-cell stage (from DP stage onward) | Cause abnormal thymic T-cell maturation and autoimmunity | 92 |
| T cells | Foxp3-Cre; Adar1f/f | Tregs | Loss of peripheral Treg loss and autoimmune disorders | 93 |
| B cells | Cd19-Cre; Adar1f/f | Late B-cell stage (from pre–B-cell stage onward) | Reduce immature B and recirculating mature B cells; elevated apoptosis and ISGs | 94,96 |
| B cells | Mb1-Cre; Adar1f/f | Early B-cell stage (from pre- to pro-B cells onward) | Regulate pro–B- to large pre–B-cell transition and regulate pre-BCR expression to control large to small pre–B-cell transition | 95 |
| B cells | Mb1-Cre; Adar1f/f; MD4Tg/+ | Drive B cell directly to BCR+ immature with a prearranged BCR transgene | Display lower expression of IgM on immature B cells | 95 |
| B cells | Aicda-Cre; Adar1f/f | Activated B cells | Exhibit defective TD Ab response and diminished GC B cells | 96 |
| Cell type . | Genetic model . | Range . | Outcomes . | References . |
|---|---|---|---|---|
| Embryonic hematopoiesis | Adar1+/− | Genome wide | Died before E14 with defects in the hematopoietic system | 81 |
| Adar1−/− | Genome wide | Died around E12 with liver integration | 82 | |
| Embryonic HSPCs | Mx1-Cre; Adarf/− | Hematopoietic system | Result in low engraftment and elicit a global IFN response | 84 |
| Adult HSPCs | SCL-Cre-ER; Adarf/- | HSCs | Reduced LT-HSC (LKS+CD34lo) number and elevated IFN signaling | 84 |
| Adult HSPCs | MSCV-Cre; Adar1f/f ER-Cre; Adar1f/f | HSPCs | Low engraftment but increased frequency of SLAM HSCs (Lin–CD48–CD150+) Increase apoptosis of differentiating HPCs (Lin–c-Kit+Sca-1–) | 85 |
| Erythropoiesis | Epor-Cre; Adar1Δ/− Epor-Cre; Adar1Δ/E861A | From Pre-Meg-E population downward | Died in utero at E14.5 Macrocytic anemia and splenomegaly | 86 |
| Myeloid cells | LysM-Cre; Adar1f/f | Myelomonocytic cells | Exhibit significantly reduced AM numbers, giant AM, and significant alveolar lipid accumulation | 86,87 |
| Macrophages | Lyz2(LysM)-Cre; Adarf/f | Macrophages | Establish an antitumor microenvironment | 88 |
| DCs | Cd11c-Cre; Adar1f/f | DCs | Fail to expand normal numbers of CD103+ DC Increase inflammatory cDC2-like cells and promote early resistance against SARS-CoV-2 infection | 87,89 |
| T cells | Lck-Cre; Adar1f/f | Early T-cell stage (from DN stage onward) | Reduce TCRβ expression but increase expression of type I ISGs in thymocytes | 90,91 |
| T cells | Cd4-Cre; Adar1f/f | Late T-cell stage (from DP stage onward) | Cause abnormal thymic T-cell maturation and autoimmunity | 92 |
| T cells | Foxp3-Cre; Adar1f/f | Tregs | Loss of peripheral Treg loss and autoimmune disorders | 93 |
| B cells | Cd19-Cre; Adar1f/f | Late B-cell stage (from pre–B-cell stage onward) | Reduce immature B and recirculating mature B cells; elevated apoptosis and ISGs | 94,96 |
| B cells | Mb1-Cre; Adar1f/f | Early B-cell stage (from pre- to pro-B cells onward) | Regulate pro–B- to large pre–B-cell transition and regulate pre-BCR expression to control large to small pre–B-cell transition | 95 |
| B cells | Mb1-Cre; Adar1f/f; MD4Tg/+ | Drive B cell directly to BCR+ immature with a prearranged BCR transgene | Display lower expression of IgM on immature B cells | 95 |
| B cells | Aicda-Cre; Adar1f/f | Activated B cells | Exhibit defective TD Ab response and diminished GC B cells | 96 |
Ab, antibody; AM, alveolar macrophages; BCR, B-cell receptor; DP, double positive; GC, germinal center; HPC, hematopoietic progenitor cell; IgM, immunoglobulin M; LT-HSC, long term HSC; Pre-Meg-E, premegakaryocyte-erythroid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCRβ, T-cell receptor beta chain; TD, T cell dependent; Treg, regulatory T cell.