Disruption of calvarial ossification in E2f4 mutant embryos correlates with increased proliferation and progenitor cell populations.
The E2F family of transcription factors, in association with pocket protein family members, are important for regulating genes required for cellular proliferation. The most abundant E2F, E2F4, is implicated in maintaining the G(0)/G(1) cell cycle state via transcriptional repression of genes that encode proteins required for S-phase progression. Here, we investigate E2F4's role in bone development using E2f4 germline mutant mice. We find that mutation of E2f4 impairs the formation of several bones that arise through intramembranous or endochondral ossification. The most severe defect occurred in the calvarial bones of the skull where we observed a striking delay in their ossification. In vivo and in vitro analyses established that E2F4 loss did not block the intrinsic differentiation potential of calvarial osteoblast progenitors. However, our data showed that E2f4 mutation elevated proliferation in the developing calvaria in vivo and it increased the endogenous pool of undifferentiated progenitor cells. These data suggest that E2F4 plays an important role in enabling osteoblast progenitors to exit the cell cycle and subsequently differentiate thereby contributing to the commitment of these cells to the bone lineage.
Miller
Emily S
ES
David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA.
Berman
Seth D
SD
Yuan
Tina L
TL
Lees
Jacqueline A
JA
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001857:Bone Matrix / Q000378:metabolism; D002356:Cartilage / Q000196:embryology / Q000473:pathology; D049109:Cell Proliferation; D050704:E2F4 Transcription Factor / Q000172:deficiency / Q000235:genetics*; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D010006:Osteoblasts / Q000201:enzymology / Q000473:pathology; D010012:Osteogenesis; D012886:Skull / Q000196:embryology* / Q000473:pathology / Q000503:physiopathology*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology*
D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; D000469:Alkaline Phosphatase