E2f1-3 are critical for myeloid development.
Hematopoietic development involves the coordinated activity of differentiation and cell cycle regulators. In current models of mammalian cell cycle control, E2f activators (E2f1, E2f2, and E2f3) are portrayed as the ultimate transcriptional effectors that commit cells to enter and progress through S phase. Using conditional gene knock-out strategies, we show that E2f1-3 are not required for the proliferation of early myeloid progenitors. Rather, these E2fs are critical for cell survival and proliferation at two distinct steps of myeloid development. First, E2f1-3 are required as transcriptional repressors for the survival of CD11b(+) myeloid progenitors, and then they are required as activators for the proliferation of CD11b(+) macrophages. In bone marrow macrophages, we show that E2f1-3 respond to CSF1-Myc mitogenic signals and serve to activate E2f target genes and promote their proliferation. Together, these findings expose dual functions for E2f1-3 at distinct stages of myeloid development in vivo, first as repressors in cell survival and then as activators in cell proliferation. In summary, this work places E2f1-3 in a specific signaling cascade that is critical for myeloid development in vivo.
College of Medicine and Public Health, Ohio State University, Columbus, Ohio 43210, USA.
Prashant
P
Trikha
Nidhi
N
Sharma
Rene
R
Opavsky
Andres
A
Reyes
Clarissa
C
Pena
Michael C
MC
Ostrowski
Martine F
MF
Roussel
Gustavo
G
Leone
D000818:Animals; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050703:E2F2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000378:metabolism*; D041681:NIH 3T3 Cells; D016196:S Phase / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
D039481:CD11b Antigen; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D050699:E2F3 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse; C490840:E2f3 protein, mouse