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Molecular and Cellular Biology, September 2009, p. 4701-4713, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01767-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The p107/E2F Pathway Regulates Fibroblast Growth Factor 2 Responsiveness in Neural Precursor Cells {triangledown}

Kelly A. McClellan,{dagger} Jacqueline L. Vanderluit,{dagger},{ddagger} Lisa M. Julian, Matthew G. Andrusiak, Delphie Dugal-Tessier, David S. Park, and Ruth S. Slack*

University of Ottawa, Department of Cellular and Molecular Medicine, 451 Smyth Rd, Ottawa, Ontario K1H 8M5, Canada

Received 18 November 2008/ Returned for modification 30 December 2008/ Accepted 14 June 2009

We have previously shown that p107, a member of the retinoblastoma (Rb) cell cycle regulatory family, has a unique function in regulating the pool of neural precursor cells. As the pool of progenitors is regulated by a limiting supply of trophic factors, we asked if the Rb/E2F pathway may control the size of the progenitor population by regulating the levels of growth factors or their receptors. Here, we demonstrate that fibroblast growth factor 2 (FGF2) is aberrantly upregulated in the brains of animals lacking Rb family proteins and that the gene encoding the FGF2 ligand is directly regulated by p107 and E2F3. Chromatin immunoprecipitation assays demonstrated that E2F3 and p107 occupy E2F consensus sites on the FGF2 promoter in the context of native chromatin. To evaluate the physiological consequence of FGF2 deregulation in both p107 and E2F3 mutants, we measured neural progenitor responsiveness to growth factors. Our results demonstrate that E2F3 and p107 are each mediators of FGF2 growth factor responsiveness in neural progenitor cells. These results support a model whereby p107 regulates the pool of FGF-responsive progenitors by directly regulating FGF2 gene expression in vivo. By identifying novel roles for p107/E2F in regulating genes outside of the classical cell cycle machinery targets, we uncover a new mechanism whereby Rb/E2F mediates proliferation through regulating growth factor responsiveness.

* Corresponding author. Mailing address: Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, ON K1H 8M5, Canada. Phone: (613) 562-5800, ext. 8458. Fax: (613) 562-5403. E-mail: rslack{at}uottawa.ca

{triangledown} Published ahead of print on 29 June 2009.

{dagger} These authors contributed equally.

{ddagger} Present address: Memorial University of Newfoundland, Division of BioMedical Sciences, St. John's, Newfoundland A1B 3V6, Canada.

Molecular and Cellular Biology, September 2009, p. 4701-4713, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01767-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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