Table 3.

Cre-loxP-mediated conditional knock-outs or knock-ins affecting erythropoiesis

Floxed allele	Gene product description	Process under investigation	Phenotype/process affected	Reference
Zbtb7a	Transcription factor: Zinc finger and BTB domain containing 7A	Hematopoietic Stem Cell (HSC) maintenance	Embryonic lethal, anemia	[52]
Myc	Transcription factor: Myc proto-oncogene protein	Primitive Hematopoiesis	Embryonic lethal, blocks HSC differentiation, absence of primitive erythrocytes	[53]
SCL/Tal-1	Transcription factor	Hematopoietic Stem Cells	Embryonic lethal, genesis of HSCs, differentiation into erythroid and megakaryocytic progenitors, anemia, thrombocytopenia	[54]
Asxl1 (also Asxl1: nlacZ/nGFP knock-in)	Transcription factor: Additional sex combs like transcriptional regulator 1	Erythropoiesis	Embryonic lethal, myelodysplastic syndrome	[55]
Meis1	Transcription factor: Homeobox protein Meis1	Erythropoiesis	Primitive hematopoietic repopulating cells and megakaryocytic/erythroid progenitor expansion, abnormal HSC function	[56]
Klf1	Transcription factor: Krüppel-like factor 1	Hemoglobin Switching	Embryonic lethal, β-like globin gene expression, anemia	[57]
Klf2	Transcription factor: Krüppel-like factor 2	Hemoglobin Switching	Embryonic lethal, β-like globin gene expression, anemia	[57]
Bcl1 1a	Transcription factor: C2H2 type zinc-finger	Hemoglobin Switching	γ-globin (HbF) repression	[58]
Mi2/β	Chromodomain helicase DNA binding protein 4	Hemoglobin Switching	γ-globin (HbF) repression	[59]
Atg7	Interacting protein: Ubiquitin - activating enzyme E1-like protein	Erythropoiesis	Mitochondrial autophagy, splenomegaly, death via severe anemia	[60]
Med1	Mediator complex subunit 1: required for SP1 activation as part of CRSP complex	Erythropoiesis	Block in erythroid development	[61]
Taf10	Interacting protein: TATA-box binding protein associated factor 10	Erythropoiesis	Embryonic lethal	[62]
Gfi 1b	Transcription factor: Growth factor independent 1 B transcription repressor	Erythropoiesis	Abnormal HSC function	[63]
Tsc 1/Rptor	Interacting protein: Tuberous sclerosis 1 interacting protein/regulatory associated protein of mTOR complex 1	Erythropoiesis	Role of mTORC1 in erythropoiesis, increased neonatal mortality, macrocytic/microcytic anemia	[64]
Ldb1	Interacting protein: LIM domain binding 1	Erythropoiesis	Embryonic lethal, abnormal erythroid gene expression, defective primitive erythropoiesis, continuously required for definitive erythropoiesis and megakaryopoiesis	[65]
Pit1	Interacting protein: Solute carrier family 20 (phosphate transporter) member 1	Erythropoiesis	Erythroid maturation, anemia, myelodysplastic syndromes	[66]
Sf3b1K700E knock-in	Interacting protein: Splicing factor 3b subunit 1	Erythropoiesis	Impaired erythropoiesis and aberrant splicing, myelodysplastic syndromes	[67]
Miz-1	Transcription factor: Myc-interacting zinc finger protein 1	Erythropoiesis	Embryonic lethal, required for embryonic and stress-induced erythropoiesis, perturbed erythroid differentiation and development, severe anemia	[68]
Brg1	Transcription factor: Brahma-related gene 1	Erythropoiesis, Vascular Development	Embryonic lethal, altered globin expression, anemia, erythropoietic/vascular abnormalities	[69]
RhoA	Hub protein: Ras homolog family member A	Erythropoiesis	Embryonic lethal, cytokinesis in erythroblasts, failed definitive erythropoiesis, anemia	[70]
Spry1	Interacting protein: Sprouty RTK signaling antagonist 1	Erythropoiesis	Perturbed erythroid development, reticulocytosis, heightened splenic erythropoiesis, regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity	[71]
Vegf	Growth factor: Vascular endothelial growth factor	Erythropoiesis	Erythropoietic lineage development, increased Gatal levels, increased erythroid differentiation	[72]
Stat5	Transcription factor: Signal transducer and activator of transcription 5A	Erythropoiesis	Reduced transferrin receptor gene expression, microcytic, hypochromic anemia	[73]
cdc42	Rho GTPase Cdc42: Cell division control protein 42 homolog	Erythropoiesis	Balance between myelopoiesis and erythropoiesis, altered gene expression, fatal myeloproliferative disorder, anemia, splenomegaly	[74]
Tfr2	Membrane protein: Transferrin receptor 2	Iron Metabolism	Liver iron overload, inadequate hepcidin levels, iron-deficient anemia	[75]
Mfrn1	Mitochondrial iron transporter: Mitoferrin-1	Iron Metabolism	Embryonic lethal, reduced erythroblast formation, severe anemia	[76]
Piga	Enzyme: Phosphatidylinositol glycan anchor biosynthesis class A	Erythropoiesis	Embryonic lethal, paroxysmal nocturnal hemoglobinuria (PNH)	[45]
Jak2V617F knock-in	Non-receptor tyrosine kinase: Janus kinase 2(JAK2)	Erythropoiesis	Polycythemia-like disease (all major features of human polycythemia vera)	[77]
Phd1, Phd2, Phd3	Enzyme: Prolyl hydroxylase domain protein 1, 2, or 3 (3 PHD isoforms)	Erythropoiesis	Erythrocytosis	[78]
Epo	Growth factor: Erythropoietin (EPO)	Erythropoiesis	Embryonic lethal, chronic, normocytic, normochromic anemia, pre-clinical model for anemia of Epo deficiency	[79]
pRb	Tumor suppressor protein: Retinoblastoma protein	Erythropoiesis	Defects in cell cycle regulation and mitochondrial function, anemia, myelodysplastic syndromes	[80]
Trim33	Transcriptional corepressor: Tripartite motif-containing 33, also known as transcriptional intermediary factor 1 gamma (TIF1-γ)	Erythropoiesis	Embryonic lethal	[81]
Bcl-x	Anti-apoptotic factor: Bcl-2-like protein 1	Erythropoiesis	Required for the survival of erythroid cells at the end of maturation, which includes enucleated reticulocytes in circulation, hemolytic anemia, hyperplasia of immature erythroid cells, splenomegaly	[82]
Nix	Pro-apoptotic factor: BH3-only-like protein	Erythropoiesis	Reticulocytosis, thrombocytosis, splenomegaly, splenic and bone marrow erythroblastosis, reduced apoptosis during erythrocyte maturation	[83]
Tr2/Tr4	Transcription factor: Testicular receptor 2 (TR2), Testicular receptor 4 (TR4)	Hemoglobin Switching	Embryonic lethal, γ-globin gene repression	[84]
Zbp-89 (Zfp148)	Transcription factor: Zinc finger protein 148	Hematopoiesis	Stress erythropoiesis, erythroid lineage development, anemia, thrombocytopenia, myeloid and B lymphoid lineage anomalies, altered HSC gene expression	[85]
Trim28	Transcriptional cofactor: Tripartite motif-containing protein 28, also known as transcriptional intermediary factor 1 beta (TIF1β)	Erythropoiesis	Cell- autonomous development of immature erythroblasts in bone marrow, essential for erythroblasts differentiation, anemia, increased apoptosis, reduced erythroid transcription factor expression, reduced heme biosynthesis	[86]
Ccbel	Lymphangiogenic factor: Collagen and calcium-binding epidermal growth factor domain-containing protein 1	Primitive Erythropoiesis	Secreted lymphangiogenic CCBE1 is essential for fetal, but not postnatal erythropoiesis, loss of CCBE1 signaling impairs erythroblastic island formation and function, not required in hematopoietic cells, severe anemia, increased apoptosis	[87]
Sur	Inhibitor of apoptosis: Survivin	Erythropoiesis	Essential for steady-state hematopoiesis and survival of adult, high level expression critical for proper erythroid differentiation, bone marrow depletion, pancytopenia, erythrocyte abnormalities, hypocellular spleen, hematopoietic cell death	[88]
Runxl	Transcription factor: Runt-related transcription factor 1	Hematopoiesis	Embryonic lethal, not required in adult hematopoietic compartment, abnormal HSCs, defective T- and B-cell maturation, inefficient platelet production, mild myeloproliferative phenotype	[89]
α4	Transmembrane receptor: α4 integrin subunit	Hematopoietic Stem Cells	Progenitor cell influx into the peripheral blood, delayed erythroid and myeloid regeneration, hematopoietic abnormalities	[90]
Raf-1	Enzyme: RAF proto-oncogene serine/threonine-protein kinase	Erythropoiesis	Embryonic lethal, anemia, accelerated erythroid differentiation	[91]
Jak2	Non-receptor tyrosine kinase: Janus kinase 2	Hematopoiesis	Embryonic lethal, impaired hematopoiesis, splenic atrophy, severely diminished erythropoiesis and thrombopoiesis, modestly affected granulopoiesis and monocytopoiesis	[92]
Abcb7	Mitochondrial ATP-binding cassette sub-family B member 7	Hematopoiesis	X-linked sideroblastic anemia with ataxia (XLSA/A) due to inhibition of heme biosynthesis, damaged mitochondria, pancytopenia, hypocellular bone marrow	[93]
Ufbp1	Inhibitor of apoptosis in ER-stressed cells: Ufm1 binding protein 1	Hematopoiesis	Embryonic lethal, impaired hematopoiesis, defective erythroid development, pancytopenia, suppressed GATA-1 and KLF1 expression	[94]
Ezh2	Enzymatic component of Polycomb Repressive Complex 2: Enhancer of zeste homolog 2	Hematopoietic Stem Cells	Embryonic lethal, essential for fetal liver, but not bone marrow erythropoiesis, defective HSC expansion, compromised lymphopoiesis, reduced H3K27me3 levels suggesting epigenetic status of HSCs is developmentally regulated, anemia	[95]
Rcor1	Transcriptional corepressor: REST (repressor element-1 silencing transcription factor) corepressor 1	Hematopoietic Stem Cells	Embryonic lethal, promotes erythropoiesis by repressing HSC and/or progenitor genes, as well as genes and signaling pathways that lead to myeloid cell fate, block in fetal erythropoiesis at the proerythroblast stage, anemia	[96]
Setd8	Histone Methyltransferase: monomethylates histone H4 lysine 20 (H4K20mel)	Erythropoiesis	Embryonic lethal, defect in primitive erythropoiesis, abnormalities in cell cycle progression, regulates erythroid maturation, represses Gata2 expression, severe anemia	[97]
Smad4	Signal transduction: Mothers against decapentaplegic homolog 4	Erythropoiesis	Not required for adult erythropoiesis, severe anemia due solely to blood loss, iron deficiency	[98]
Ulk1	Enzyme: Serine/threonine-protein kinase	Erythropoiesis	Autophagy machinery that leads to the elimination of organelles in erythroid cells	[99]
Ck2β	Enzyme: serine-threonine kinase composed of two catalytic (α) and two regulatory (β) subunits	Hematopoiesis	Embryonic lethal, regulates definitive hematopoiesis of all hematopoietic cell lineages	[100]
Flvcr1a	Heme exporter membrane protein: Feline leukemia virus subgroup C receptor 1	Erythropoiesis	Embryonic lethal, heme export control, severe macrocytic anemia, splenomegaly, iron accumulation in duodenum, liver and spleen, reduced BFU-E and CFU-E, defective erythroid differentiation	[101]
Rhau	RNA helicase: RNA helicase associated with AU-rich element	Hematopoiesis	Embryonic lethal, hemolytic anemia, differentiation defect at the proerythroblast stage	[102]
Add3	Adducins: Skeletal protein involved in the assembly of spectrin-actin network	RBC membrane skeleton structure	Animals were viable and presented no obvious erythroid cell defects	[103]
cyclin ET74A T393A knock-in	Cell cycle regulator: Complexes with the CDK2 cyclin-dependent kinase subunit	Erythropoiesis	Links ubiquitin-proteasome pathway control of G1-to-S-phase progression to regulation of metabolism and gene expression in terminally differentiating bone marrow erythroid cells, abnormal erythropoiesis characterized by a large expansion of abnormally proliferating progenitors, impaired differentiation, dysplasia, and anemia, models early stage human refractory anemia/myelodysplastic syndrome	[104]
Rps14	40S ribosomal subunit protein S14	Erythropoiesis	Erythroid differentiation defect dependent on p53 characterized by apoptosis during transition from polychromatic to orthochromatic erythroblasts, age-dependent progressive anemia, megakaryocyte dysplasia, block in erythroid differentiation, loss of HSC quiescence	[105]
Rps6	40s Ribosomal subunit protein S6	Erythropoiesis	Hypoproliferative macrocytic anemia, granulocytopenia, thrombocytosis, lymphopenia (model for Diamond-Blackfan Anemia and myelodysplastic syndrome)	[106]
Ppp2ca	Enzyme: Serine/threonine phosphatase, protein phosphatase 2A	Erythropoiesis	Perturbed definitive erythropoiesis characterized by fetal liver atrophy, reduced Terll9+ cell number, atypical expression patterns of molecular markers, reduced colony formation, reduction in definitive globin gene expression	[107]
Dicer	Enzyme: Endoribonuclease	Hematopoietic Stem Cells	Down-regulation of erythroid genes, defective erythroid linage differentiation	[108]
Ml1	Enzyme: Mixed-lineage leukemia	Hematopoietic Stem Cells	Embryonic lethal, reduced numbers of HSCs, abnormal HSC function	[109]
Ufm1	Ubiquitin-like modification system: Ubiquitin-fold modifier 1	Hematopoietic Stem Cells	Embryonic lethal, diminished hematopoietic development, increased HSC death, severe anemia, cytopenia, elevated endoplasmic reticulum stress, blocked autophagic degradation, increased ROS	[110]
Rac1, Rac2	Rac GTPases: Racl and Rac2 regulates many aspects of intracellular actin dynamics	Erythropoiesis	Abnormal BFU-E and CFU-E morphology, decreased megakaryocyte-erythrocyte progenitors in bone marrow, increased splenic erythropoiesis	[111]
Adar1	RNA-editing enzyme: Adenosine deaminase acting on RNA 1	Hematopoietic Stem Cells	Embryonic lethal, abnormal HSC function, increased HSC apoptosis	[112]
Sod2	Enzyme: Superoxide dismutase 2	Hematopoietic Stem Cells	Increased ROS in erythroid progeny, diminished erythrocytes, decreased ferrochelatase activity, extramedullary hematopoiesis, systemic iron redistribution, abnormal gene expression (hematopoietic transcription factors, globins, and iron-response genes), changes in histone posttranslational modification	[113]