Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1/E2F2 mutant mice.
E2F plays critical roles in cell cycle progression by regulating the expression of genes involved in nucleotide synthesis, DNA replication, and cell cycle control. We show that the combined loss of E2F1 and E2F2 in mice leads to profound cell-autonomous defects in the hematopoietic development of multiple cell lineages. E2F2 mutant mice show erythroid maturation defects that are comparable with those observed in patients with megaloblastic anemia. Importantly, hematopoietic defects observed in E2F1/E2F2 double-knockout (DKO) mice appear to result from impeded S phase progression in hematopoietic progenitor cells. During DKO B-cell maturation, differentiation beyond the large pre-BII-cell stage is defective, presumably due to failed cell cycle exit, and the cells undergo apoptosis. However, apoptosis appears to be the consequence of failed maturation, not the cause. Despite the accumulation of hematopoietic progenitor cells in S phase, the combined loss of E2F1 and E2F2 results in significantly decreased expression and activities of several E2F target genes including cyclin A2. Our results indicate specific roles for E2F1 and E2F2 in the induction of E2F target genes, which contribute to efficient expansion and maturation of hematopoietic progenitor cells. Thus, E2F1 and E2F2 play essential and redundant roles in the proper coordination of cell cycle progression with differentiation which is necessary for efficient hematopoiesis.
Li
Feng X
FX
Department of Biochemistry and Molecular Genetics, Division of Medical Oncology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Zhu
Jing W
JW
Hogan
Christopher J
CJ
DeGregori
James
J
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D019070:Cell Lineage; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004920:Erythropoiesis; D005434:Flow Cytometry; D005838:Genotype; D049452:Green Fluorescent Proteins; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding; D016196:S Phase; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D008164:Luminescent Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine