Rb/E2F regulates expression of neogenin during neuronal migration.
The Rb/E2F pathway has long been appreciated for its role in regulating cell cycle progression. Emerging evidence indicates that it also influences physiological events beyond regulation of the cell cycle. We have previously described a requirement for Rb/E2F mediating neuronal migration; however, the molecular mechanisms remain unknown, making this an ideal system to identify Rb/E2F-mediated atypical gene regulation in vivo. Here, we report that Rb regulates the expression of neogenin, a gene encoding a receptor involved in cell migration and axon guidance. Rb is capable of repressing E2F-mediated neogenin expression while E2F3 occupies a region containing E2F consensus sites on the neogenin promoter in native chromatin. Absence of Rb results in aberrant neuronal migration and adhesion in response to netrin-1, a known ligand for neogenin. Increased expression of neogenin through ex vivo electroporation results in impaired neuronal migration similar to that detected in forebrain-specific Rb deficiency. These findings show direct regulation of neogenin by the Rb/E2F pathway and demonstrate that regulation of neogenin expression is required for neural precursor migration. These studies identify a novel mechanism through which Rb regulates transcription of a gene beyond the classical E2F targets to regulate events distinct from cell cycle progression.
Department of Cellular Molecular Medicine, University of Ottawa, 451 Smyth Rd., Ottawa, Ontario K1H 8M5, Canada.
Matthew G
MG
Andrusiak
Kelly A
KA
McClellan
Delphie
D
Dugal-Tessier
Lisa M
LM
Julian
Sonia P
SP
Rodrigues
David S
DS
Park
Timothy E
TE
Kennedy
Ruth S
RS
Slack
D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D016548:Prosencephalon / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D050699:E2F3 Transcription Factor; D008565:Membrane Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; C091279:neogenin; D000075388:Netrin-1