The mammalian nervous system has no mechanisms to replace lost neurons except in some regions where neurogenesis continues throughout life. Transfection of E1A- and E2F1-expressing plasmids into cerebellar granular neurons of mice in vitro stimulated 37 and 43%, respectively, of the successfully transfected neurons to become BrdU-positive 24 h after transfection. Furthermore, immunoliposome-mediated transfection of E1A- and E2F1-expressing plasmids into the adult cortical neurons of rats in vivo resulted in initiation of DNA synthesis in 15 and 5% of the transfected neurons after 33 and 55 h of transfection, respectively. Our findings suggest that either the over-expression of E2F1 or the release of endogenous E2F1 after expression of E1A overcomes the retinoblastoma (Rb) tumor suppressor gene which blocks the cell cycle in neurons and allows neurons to initiate DNA synthesis.