Unique requirement for Rb/E2F3 in neuronal migration: evidence for cell cycle-independent functions.
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.
McClellan
Kelly A
KA
Department of Cellular and Molecular Medicine, Ottawa Health Research Institute, University of Ottawa, Ottawa, ON, Canada.
Ruzhynsky
Vladimir A
VA
Douda
David N
DN
Vanderluit
Jacqueline L
JL
Ferguson
Kerry L
KL
Chen
Danian
D
Bremner
Rod
R
Park
David S
DS
Leone
Gustavo
G
Slack
Ruth S
RS
D000818:Animals; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D050687:E2F1 Transcription Factor / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007395:Interneurons / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D016160:Retinoblastoma Protein / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013687:Telencephalon / Q000196:embryology / Q000378:metabolism
D050687:E2F1 Transcription Factor; D050699:E2F3 Transcription Factor; D008565:Membrane Proteins; D016160:Retinoblastoma Protein; C091279:neogenin