Loss of E2F4 Activity Leads to Abnormal Development of Multiple Cellular Lineages

Abstract

We have generated mice deficient in E2F4 activity, the major form of E2F in many cell types. Analysis of newborn pups deficient in E2F4 revealed abnormalities in hematopoietic lineage development as well as defects in the development of the gut epithelium. Specifically, we observed a deficiency of various mature hematopoietic cell types together with an increased number of immature cells in several lineages. This was associated with an increased frequency of apoptotic cells. We also found a substantial reduction in the thickness of the gut epithelium that normally gives rise to crypts as well as a reduction in the density of villi. These observations suggest a critical role for E2F4 activity in controlling the maturation of cells in a number of tissues.

E2F4 Modulates Differentiation and Gene Expression in Hematopoietic Progenitor Cells during Commitment to the Lymphoid Lineage

“…Among these, E2F4 is found at high concentrations in hemopoietic cells (15). Overexpression of E2F4 promotes terminal differentiation of cells in vitro (16), whereas E2F4-deficient animals show reduced neonatal viability, with very few animals surviving to adulthood (15,17).…”

“…Among these, E2F4 is found at high concentrations in hemopoietic cells (15). Overexpression of E2F4 promotes terminal differentiation of cells in vitro (16), whereas E2F4-deficient animals show reduced neonatal viability, with very few animals surviving to adulthood (15,17). These animals died due to opportunistic infections and anemia, but they were also smaller than either heterozygous or wild-type (WT) littermates (15,17).…”

“…Overexpression of E2F4 promotes terminal differentiation of cells in vitro (16), whereas E2F4-deficient animals show reduced neonatal viability, with very few animals surviving to adulthood (15,17). These animals died due to opportunistic infections and anemia, but they were also smaller than either heterozygous or wild-type (WT) littermates (15,17). Recently, E2F4 has been shown to play a role during fetal erythropoiesis, explaining the anemia that is seen in the fetuses and neonates (18).…”

“…Recently, E2F4 has been shown to play a role during fetal erythropoiesis, explaining the anemia that is seen in the fetuses and neonates (18). However, the impact of E2F4 deficiency on thymocyte development has been controversial (15,17). Both the erythroid and the lymphoid defects in E2F4-deficient mice could be explained if the defect occurred at the level of the HSC, which gives rise to both lineages.…”

“…On day 14.5 of gestation, fetal livers were mechanically disrupted to make single cell suspensions, and a small amount of fetal tissue was taken for PCR genotyping. DNA was isolated using the Qiagen DNeasy kit, following the manufacturer's instructions, and PCR was conducted using previously described primers (15). Fetal liver cells were resuspended at a concentration of 2.5 ϫ 10 6 cells/ml in sterile PBS.…”