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Molecular and Cellular Biology, July 2007, p. 4825-4843, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02100-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Unique Requirement for Rb/E2F3 in Neuronal Migration: Evidence for Cell Cycle-Independent Functions

Kelly A. McClellan,¹ Vladimir A. Ruzhynsky,¹ David N. Douda,¹ Jacqueline L. Vanderluit,¹ Kerry L. Ferguson,¹ Danian Chen,² Rod Bremner,² David S. Park,¹ Gustavo Leone,³ and Ruth S. Slack^1*

Department of Cellular and Molecular Medicine, Neurosciences Program, University of Ottawa, and Ottawa Health Research Institute, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5,¹ Toronto Western Research Institute, University Health Network, Vision Science Research Program, Departments of Ophthalmology and Vision Science and of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5T 2S8,² Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics and Department of Molecular Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210³

Received 9 November 2006/ Returned for modification 12 December 2006/ Accepted 10 April 2007

The cell cycle regulatory retinoblastoma (Rb) protein is a key regulator of neural precursor proliferation; however, its role has been expanded to include a novel cell-autonomous role in mediating neuronal migration. We sought to determine the Rb-interacting factors that mediate both the cell cycle and migration defects. E2F1 and E2F3 are likely Rb-interacting candidates that we have shown to be deregulated in the absence of Rb. Using mice with compound null mutations of Rb and E2F1 or E2F3, we asked to what extent either E2F1 or E2F3 interacts with Rb in neurogenesis. Here, we report that E2F1 and E2F3 are both functionally relevant targets in neural precursor proliferation, cell cycle exit, and laminar patterning. Each also partially mediates the Rb requirement for neuronal survival. Neuronal migration, however, is specifically mediated through E2F3, beyond its role in cell cycle regulation. This study not only outlines overlapping and distinct functions for E2Fs in neurogenesis but also is the first to establish a physiologically relevant role for the Rb/E2F pathway beyond cell cycle regulation in vivo.

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

Published ahead of print on 23 April 2007.

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Molecular and Cellular Biology, July 2007, p. 4825-4843, Vol. 27, No. 13
0270-7306/07/$08.00+0     doi:10.1128/MCB.02100-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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