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The E2f transcription factors are key downstream targets of the retinoblastoma protein tumor suppressor that control cell proliferation. E2F3 has garnered particular attention because it is amplified in various human tumors. E2f3 mutant mice typically die around birth and E2f3-deficient cells have a proliferation defect that correlates with impaired E2f target gene activation and also induction of p19(Arf) and p53. The E2f3 locus encodes two isoforms, E2f3a and E2f3b, which differ in their N-termini. However, it is unclear how E2f3a versus E2f3b contributes to E2f3's requirement in either proliferation or development. To address this, we use E2f3a- and E2f3b-specific knockouts. We show that inactivation of E2f3a results in a low penetrance proliferation defect in vitro whereas loss of E2f3b has no effect. This proliferation defect appears insufficient to disrupt normal development as E2f3a and E2f3b mutant mice are both fully viable and have no detectable defects. However, when combined with E2f1 mutation, inactivation of E2f3a, but not E2f3b, causes significant proliferation defects in vitro, neonatal lethality and also a striking cartilage defect. Thus, we conclude that E2f3a and E2f3b have largely overlapping functions in vivo and that E2f3a can fully substitute for E2f1 and E2f3 in most murine tissues.

E2f3a and E2f3b make overlapping but different contributions to total E2f3 activity