The Rb/E2F pathway modulates neurogenesis through direct regulation of the Dlx1/Dlx2 bigene cluster.
During brain morphogenesis, the mechanisms through which the cell cycle machinery integrates with differentiation signals remain elusive. Here we show that the Rb/E2F pathway regulates key aspects of differentiation and migration through direct control of the Dlx1 and Dlx2 homeodomain proteins, required for interneuron specification. Rb deficiency results in a dramatic reduction of Dlx1 and Dlx2 gene expression manifested by loss of interneuron subtypes and severe migration defects in the mouse brain. The Rb/E2F pathway modulates Dlx1/Dlx2 regulation through direct interaction with a Dlx forebrain-specific enhancer, I12b, and the Dlx1/Dlx2 proximal promoter regions, through repressor E2F sites both in vitro and in vivo. In the absence of Rb, we demonstrate that repressor E2Fs inhibit Dlx transcription at the Dlx1/Dlx2 promoters and Dlx1/2-I12b enhancer to suppress differentiation. Our findings support a model whereby the cell cycle machinery not only controls cell division but also modulates neuronal differentiation and migration through direct regulation of the Dlx1/Dlx2 bigene cluster during embryonic development.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Noël
N
Ghanem
Matthew G
MG
Andrusiak
Devon
D
Svoboda
Sawsan M
SM
Al Lafi
Lisa M
LM
Julian
Kelly A
KA
McClellan
Yves
Y
De Repentigny
Rashmi
R
Kothary
Marc
M
Ekker
Alexandre
A
Blais
David S
DS
Park
Ruth S
RS
Slack
D000818:Animals; D001921:Brain / Q000254:growth & development / Q000502:physiology; D002452:Cell Count / Q000379:methods; D050684:E2F Transcription Factors / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D007395:Interneurons / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000502:physiology*; D011247:Pregnancy; D016160:Retinoblastoma Protein / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis*
C088334:Distal-less homeobox proteins; D050684:E2F Transcription Factors; D018398:Homeodomain Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors