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The Journal of Neuroscience, May 30, 2007, 27(22):5926-5935; doi:10.1523/JNEUROSCI.1538-07.2007

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Development/Plasticity/Repair
Cell Cycle Regulator E2F4 Is Essential for the Development of the Ventral Telencephalon

Vladimir A. Ruzhynsky,¹ Kelly A. McClellan,¹ Jacqueline L. Vanderluit,¹ Yongsu Jeong,⁴ Marosh Furimsky,^2,3 David S. Park,¹ Douglas J. Epstein,⁴ Valerie A. Wallace,^2,3 and Ruth S. Slack¹

¹Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, Neuroscience Program, and ²Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5, ³Molecular Medicine Program and Vision Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8L6, and ⁴Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Ruth S. Slack, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: rslack{at}uottawa.ca

Early forebrain development is characterized by extensive proliferation of neural precursors coupled with complex structural transformations; however, little is known regarding the mechanisms by which these processes are integrated. Here, we show that deficiency of the cell cycle regulatory protein, E2F4, results in the loss of ventral telencephalic structures and impaired self-renewal of neural precursor cells. The mechanism underlying aberrant ventral patterning lies in a dramatic loss of Sonic hedgehog (Shh) expression specifically in this region. The E2F4-deficient phenotype can be recapitulated by interbreeding mice heterozygous for E2F4 with those lacking one allele of Shh, suggesting a genetic interaction between these pathways. Treatment of E2F4-deficient cells with a Hh agonist rescues stem cell self-renewal and cells expressing the homeodomain proteins that specify the ventral telencephalic structures. Finally, we show that E2F4 deficiency results in impaired activity of Shh forebrain-specific enhancers. In conclusion, these studies establish a novel requirement for the cell cycle regulatory protein, E2F4, in the development of the ventral telencephalon.

Key words: E2F4; cell cycle; Sonic hedgehog; neural precursors; neural patterning; telencephalon

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Received Aug. 8, 2006; accepted April 23, 2007.

Correspondence should be addressed to Ruth S. Slack, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Email: rslack{at}uottawa.ca

This article has been cited by other articles:

				N. Arbour, J. L. Vanderluit, J. N. Le Grand, A. Jahani-Asl, V. A. Ruzhynsky, E. C. C. Cheung, M. A. Kelly, A. E. MacKenzie, D. S. Park, J. T. Opferman, et al. Mcl-1 Is a Key Regulator of Apoptosis during CNS Development and after DNA Damage J. Neurosci., June 11, 2008; 28(24): 6068 - 6078. [Abstract] [Full Text] [PDF]

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