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Molecular and Cellular Biology, September 1999, p. 6048-6056, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

E2F4 Actively Promotes the Initiation and Maintenance of Nerve Growth Factor-Induced Cell Differentiation

Stephan P. Persengiev, Ivanela I. Kondova,dagger and Daniel L. Kilpatrick*

Department of Cellular and Molecular Physiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Received 16 December 1998/Returned for modification 10 February 1999/Accepted 22 February 1999

E2F transcription factors play a critical role in cell cycle progression through the regulation of genes required for G1/S transition. They are also thought to be important for growth arrest; however, their potential role in the cell differentiation process has not been previously examined. Here, we demonstrate that E2F4 is highly upregulated following the neuronal differentiation of PC12 cells with nerve growth factor (NGF), while E2F1, E2F3, and E2F5 are downregulated. Immunoprecipitation and subcellular fractionation studies demonstrated that both the nuclear localization of E2F4 and its association with the Rb family member p130 increased following neuronal differentiation. The forced expression of E2F4 markedly enhanced the rate of PC12 cell differentiation induced by NGF and also greatly lowered the rate at which cells lost their neuronal phenotype following NGF removal. Importantly, this effect occurred in the absence of any significant change in the growth regulation of PC12 cells by NGF. Further, the downregulation of E2F4 expression with antisense oligodeoxynucleotides inhibited NGF-induced neurite outgrowth, indicating an important role for this factor during PC12 cell differentiation. Finally, E2F4 expression was found to increase dramatically in the developing rat cerebral cortex and cerebellum, as neuroblasts became postmitotic and initiated terminal differentiation. These findings demonstrate that, in addition to its effects on cell proliferation, E2F4 actively promotes the neuronal differentiation of PC12 cells as well as the retention of this state. Further, this effect is independent of alterations in cell growth and may involve interactions between E2F4 and the neuronal differentiation program itself. E2F4 may be an important participant in the terminal differentiation of neuroblasts.

* Corresponding author. Mailing address: Department of Cellular and Molecular Physiology, University of Massachusetts Medical School, 55 Lake Ave. North, Worcester, MA 01655. Phone: (508) 856-6274. Fax: (508) 856-5997. E-mail: daniel.kilpatrick{at}ummed.edu.

dagger Present address: Division of Infectious Diseases, Tufts University School of Veterinary Medicine, North Grafton, MA 01536.

Molecular and Cellular Biology, September 1999, p. 6048-6056, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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