pRB and E2F4 play distinct cell-intrinsic roles in fetal erythropoiesis.
The retinoblastoma tumor suppressor protein pRB functions, at least in part, by directly binding to and modulating the activity of the E2F transcription factors. Previous studies have shown that both E2F4 and pRB play important roles in fetal erythropoiesis. Given that these two proteins interact directly we investigated the overlap of E2F4 and pRB function in this process by analyzing E2f4(-/-), conditional Rb knockout (Rb(1lox/1lox)), and compound E2f4(-/-);Rb(1lox/1lox) embryos. At E15.5 E2f4(-/-) and Rb(1lox/1lox) fetal erythroid cells display distinct abnormalities in their differentiation profiles. When cultured in vitro, both E2f4(-/-) and Rb(1lox/1lox) erythroid cells show defects in cell cycle progression. Surprisingly, analysis of cell cycle profiling suggests that E2F4 and pRB control cell cycle exit through different mechanisms. Moreover, only pRB, but not E2F4, promotes cell survival in erythroid cells. We observed an additive rather than a synergistic impact upon the erythroid defects in the compound E2f4(-/-);Rb(1lox/1lox) embryos. We further found that fetal liver macrophage development is largely normal regardless of genotype. Taken together, our results show that E2F4 and pRB play independent cell-intrinsic roles in fetal erythropoiesis.
Zhang
Jing
J
Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA, USA.
Lee
Eunice Y
EY
Liu
Yangang
Y
Berman
Seth D
SD
Lodish
Harvey F
HF
Lees
Jacqueline A
JA
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology; D041905:Erythroid Cells / Q000166:cytology*; D004920:Erythropoiesis; D005333:Fetus; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D050704:E2F4 Transcription Factor; D016160:Retinoblastoma Protein