Cell cycle regulator E2F4 is essential for the development of the ventral telencephalon.
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.
Ruzhynsky
Vladimir A
VA
Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, Neuroscience Program, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5.
McClellan
Kelly A
KA
Vanderluit
Jacqueline L
JL
Jeong
Yongsu
Y
Furimsky
Marosh
M
Park
David S
DS
Epstein
Douglas J
DJ
Wallace
Valerie A
VA
Slack
Ruth S
RS
D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002478:Cells, Cultured; D050704:E2F4 Transcription Factor / Q000172:deficiency / Q000502:physiology*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011247:Pregnancy; D013687:Telencephalon / Q000166:cytology / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*
D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse